count source_label source_id relationship target_label target_id entity_type solr_id publication_id sentences 42 UNIPROT:P05231 decreases IP:IPR000971 IP:IPR000971 Protein 57fc359c-cc76-11e5-b6ad-001a4ae51246 9242673 The expression of GATA-1 was unaffected by increasing concentrations of IL-6 (data not shown) which suggests that the down-regulation of γ globin gene expression by exogenous IL-6 is independent of significant changes in GATA-1 gene activity levels.|||To determine whether the down-regulation of γ globin gene expression by IL-6 was accompanied by an increase in MK-specific markers, studies were performed to analyze the level of GpIIb gene expression, an early marker for commitment to the MK lineage (25).|||Molecular Mechanisms Involved in the Down-regulation of γ Globin Gene Expression by IL-6 The 5′ hypersensitive sites (5′HS) of the β globin LCR are required for high level expression of the globin genes (29-32).|||Experiments were completed to investigate possible molecular mechanisms for inhibition of globin gene expression by IL-6. 40 UNIPROT:P05231 increases IP:IPR000971 IP:IPR000971 Protein 57fc359c-cc76-11e5-b6ad-001a4ae51246 9242673 The expression of GATA-1 was unaffected by increasing concentrations of IL-6 (data not shown) which suggests that the down-regulation of γ globin gene expression by exogenous IL-6 is independent of significant changes in GATA-1 gene activity levels.|||To determine whether the down-regulation of γ globin gene expression by IL-6 was accompanied by an increase in MK-specific markers, studies were performed to analyze the level of GpIIb gene expression, an early marker for commitment to the MK lineage (25).|||Molecular Mechanisms Involved in the Down-regulation of γ Globin Gene Expression by IL-6 The 5′ hypersensitive sites (5′HS) of the β globin LCR are required for high level expression of the globin genes (29-32). 32 UNIPROT:P01033 activates IP:IPR000971 IP:IPR000971 Protein ebdbcd7c-7739-11e6-b946-001a4ae51247 10.1074/jbc.272.13.8149 In several artificial systems,e.g.Ba/F3 sublines expressing exogenous EPOR (31,32), IL3 suppressed EPO-induced globin synthesis.|||Whereas EPO induced globin synthesis in TSA8 cells, EPO alone was incapable of inducing more mature differentiation, such as hemoglobin synthesis or extrusion of the nucleus. 18 UNIPROT:P00387 inhibits IP:IPR000971 IP:IPR000971 Protein 8d507628-abae-11e6-9236-001a4ae51247 PMC4505432 Our results show that the rate of α globin reduction by CYB5R3 was significantly inhibited with ZINC05626394 and ZINC39395747 (Fig. 4f).|||Recent evidence has demonstrated that loss of endothelial cell CYB5R3 increases NO bioavailability in the vascular wall by regulating the redox state of α globin (10). 18 CHEBI:46024 increases IP:IPR000971 IP:IPR000971 Chemical 0831b182-bbf9-11e5-9b9d-001a4ae51247 10.1016/S1079-9796(03)00024-X Increased amounts of TSA caused increased levels of β globin expression and reactivated the developmentally silenced γ globin gene in post-switch hybrids.|||TSA reactivates γ globin expression in post-switch hybrids We examined whether developmentally silenced γ globin gene expression can be reactivated by treating post-switch hybrids with the histone deacetylase inhibitor, trichostatin A. Previously published reports indicated that TSA would cause the induction of differentiation and the expression of murine globin in MEL cells at 10–15 nM[12].|||In contrast to the activation of γ globin expression by TSA in the post-switch hybrids there was no effect on β globin expression in the pre-switch hybrids.|||We examined whether developmentally silenced γ globin gene expression can be reactivated by treating post-switch hybrids with the histone deacetylase inhibitor, trichostatin A. Previously published reports indicated that TSA would cause the induction of differentiation and the expression of murine globin in MEL cells at 10–15 nM[12].|||TSA does not modulate globin gene expression in pre-switch hybrids Pre-switch hybrids were also treated with TSA for 3 days to examine any effects on γ or β globin expression. 16 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q9TLS1 Protein 1f00202e-c46e-11e5-a92e-001a4ae51246 PMC4118117 In both cases, reduction of the globin domain was completely abrogated, indicating the requirement of Pre-A in regulating the CD loop of HbN for establishing the intermolecular contacts with the reductase for the catalytic electron cycling required for NOD function (Fig. 8B). 16 IP:IPR000971 IP:IPR000971 activates GO:0030154 Phenotype 12012eae-201c-11e6-bd85-001a4ae51247 10.1074/jbc.272.24.15293 To elucidate whether HSF2 activity is involved in the hemin-induced erythroid differentiation, the globin content was determined in HSF2-α and HSF2-β transfectants. 16 IP:IPR000971 IP:IPR000971 activates FPLX:EIF4A ProteinFamily 2de383e4-cbf1-11e5-b0dd-001a4ae51247 10364207 For example, mammalian eIF4A, which is required for translation initiation of all mRNAs, is more effectively stimulated by poly(U) than by globin mRNA (35). 16 UNIPROT:P21583 increases IP:IPR000971 IP:IPR000971 Protein 1d599dfe-d9fa-11ee-9133-0050569a1f61 10.1182/blood.V92.4.1104 Interestingly, DAF (fig 8C) and Western blot analyses (R.C.G., data not shown) showed that SCF exerted a dose-dependent inhibition of Epo-induced globin expression and SKT6 cell hemoglobinization. 16 CHEBI:84615 activates IP:IPR000971 IP:IPR000971 Chemical 744d5588-47e5-11e6-b7df-001a4ae51246 10.1074/jbc.273.38.24861 (Sp)-cAMPS significantly prolonged the half-life of hybrid globin/ldh mRNA (panel A,lane Sp-cAMPS) but not that of wild-type globin mRNA (not shown). 16 FPLX:NFE increases IP:IPR000971 IP:IPR000971 ProteinFamily 9d7ee13e-ca5d-11e5-a3f7-001a4ae51246 12509425 From these results, we speculate that NF-E2 first binds directly to the tandem MAREs at HS2 on the chromatin structure, then remodels the chromatin structure in the presence of remodeling factors and ATP, and enhances the globin gene expression. 16 FPLX:PKA activates IP:IPR000971 IP:IPR000971 ProteinFamily 744d5588-47e5-11e6-b7df-001a4ae51246 10.1074/jbc.273.38.24861 The results summarized in TableIshow that (Rp)-cAMPS blocks protein kinase A-mediated stabilization of globin/ldh mRNA. 16 UNIPROT:P04040 activates IP:IPR000971 IP:IPR000971 Protein cdbda9d4-cb8e-11e5-9498-001a4ae51246 10734073 As previously reported (23), translation of FMDV-CAT RNA yielded the normal size CAT protein (which comigrated with CAT produced using the globin 5′-UTR, Fig.10,lane h) which initiated from the downstream AUG, and a larger product (preCAT), which initiated from the upstream AUG (lane a). 16 CHEBI:84622 inhibits IP:IPR000971 IP:IPR000971 Chemical 744d5588-47e5-11e6-b7df-001a4ae51246 10.1074/jbc.273.38.24861 The results summarized in TableIshow that (Rp)-cAMPS blocks protein kinase A-mediated stabilization of globin/ldh mRNA. 16 UNIPROT:P05231 inhibits IP:IPR000971 IP:IPR000971 Protein 57fc359c-cc76-11e5-b6ad-001a4ae51246 9242673 The protein analysis indicates that IL-6 inhibits the production of γ globin chains in K562 cells which correlates with the results obtained for γ globin mRNA production. 16 UNIPROT:P05231 activates IP:IPR000971 IP:IPR000971 Protein 57fc359c-cc76-11e5-b6ad-001a4ae51246 9242673 Thus, exogenous IL-6 treatment in K562 cells resulted in decreased γ globin gene expression, which was abrogated by monoclonal antibodies to IL-6, and decreased γ globin chain biosynthesis. 16 MESH:D006427 activates IP:IPR000971 IP:IPR000971 Phenotype 12012eae-201c-11e6-bd85-001a4ae51247 10.1074/jbc.272.24.15293 As shown in Fig.5, overexpression of HSF2-β decreased the hemin-induced globin accumulation by 40–60% (2β-D5,2β-E7), whereas globin induction was potentiated in HSF2-α-overexpressing cells (2α-F4,2α-C7). 12 UNIPROT:P12807 increases IP:IPR000971 IP:IPR000971 Protein c7b984c2-bbe4-11e5-8abe-001a4ae51246 10.1016/j.ydbio.2006.08.010 While the inhibition of globin expression by A-MO was consistently observed, faint expression of globin persisted even at the higher level of injected A-MO in many embryos (for example,Fig. 7B).|||These effects on Nkx2.5 and globin expression by A-MO were dose-dependent, and injection of 5 ng/blastomere of A-MO decreased the percentage of affected embryos in both cases to 64% and 44%, respectively (Table 1). 10 UNIPROT:P60568 increases IP:IPR000971 IP:IPR000971 Protein e25235a2-bbff-11e5-9b9d-001a4ae51247 PMC1973161 We examined whether the A-mutant, which lacks inhibitory signaling for globin gene expression, can mediate globin gene expression by IL-2.|||IL-2 did not induce globin gene expression in cells expressing the A-mutant of IL-2Rβ (Fig. 4D), suggesting that a signaling pathway(s) specifically induced by EpoR may be necessary to induce erythroid differentiation and globin gene expression.|||Furthermore, we showed that IL-2 also mediates inhibition of Epo-induced globin gene expression, for which the acidic region (the A-region) of the IL-2 receptor (IL-2) β-chain (IL-2Rβ) is essential for this inhibition. 10 MESH:D006427 inhibits IP:IPR000971 IP:IPR000971 Phenotype 4e239d6a-cbf1-11e5-83a8-001a4ae51246 10082971 These results are consistent with earlier studies of hemin addition to intact normal andb/breticulocytes[12]in which the exogenous hemin inhibited globin synthesis in the normal controls (where presumably endogenous heme is optimal), but stimulated globin synthesis in the heme-deficient Belgrade cells.|||The earlier studies[12]showed that globin synthesis in intactb/breticulocytes was stimulated by exogenous hemin, but globin synthesis in control rat reticulocytes was inhibited by exogenous hemin.|||Addition of exogenous hemin stimulated globin synthesis in intactb/breticulocytes, but inhibited globin synthesis in normal reticulocytes[12]. 9 FPLX:STAT5 increases IP:IPR000971 IP:IPR000971 ProteinFamily e25235a2-bbff-11e5-9b9d-001a4ae51247 PMC1973161 Since overexpression of Stat5 did not support globin gene expression in BBLG stimulated with EGF (data not shown), enhanced transcriptional activity by Gal4 TA is necessary for EGF-induced globin gene expression.|||Epo induces sustained activation of Stat5 Considering that sustained activation of Stat5-induced globin gene expression as shown above, we investigated whether Epo supports sustained activation of Stat5.|||Sustained activation of Stat5 induces globin gene expression To examine the consequence of sustained activation of Stat5, we analyzed the genome-wide gene expression profile of BBLG expressing LG-Stat5 using DNA microarray analysis.|||These results indicate that sustained activation of Stat5 mediates erythroid differentiation and globin gene expression. 8 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 6156a34a-e80e-11ee-8b99-0050569a1f61 10.1182/blood.V4.5.479.479 Goodman and Gilman32offered as a probable explanation of the action of phenylhydrazine on the erythrocyte the splitting of the hemoglobin into hemin and globin, at least a portion of the remaining hemoglobin being catalyzed by the globin to form methemoglobin and perhaps other unidentified substances. 8 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily de290948-bbd6-11e5-956b-001a4ae51247 PMC2280037 As described by Max Perutz in the 1980s, a single amino acid change in globin increases the affinity of hemoglobin for oxygen in high-altitude migrating geese compared to their common low-flying relatives (Hoekstra and Coyne, 2007). 8 IP:IPR000971 IP:IPR000971 inhibits GO:0070527 Phenotype 74544942-2c51-11f0-bb75-0050569a1f61 10.1016/S0049-3848(02)00346-8 Globin inhibited platelet aggregation in a concentration-dependent manner, irrespective of the agonists, i.e., ADP, AA, calcium ionophore A23187, which were used to induce aggregation(Fig. 4).|||Interestingly, globin inhibited ADP-, AA- or A23187-induced platelet aggregation in a concentration-dependent manner. 8 IP:IPR000971 IP:IPR000971 inhibits GO:0042167 Phenotype 2822bcf6-bc40-11e5-8d2d-001a4ae51247 10.1016/j.freeradbiomed.2007.06.013 This suggests that the globin moiety of MbFeIIImoderately inhibits heme degradation only when both species are bound (pH 5.8).|||In fact, the globin-bound heme of metmyoglobin mainly induces the heterolytic cleavage of LOOH to yield another likely precursor of heme degradation, Mb+FeIVO[31–33], in which the porphyrin radical cation partially escapes reduction by the antioxidant as evidenced by the partial heme degradation during the lag phase. 8 PF:PF08659 activates IP:IPR000971 IP:IPR000971 ProteinFamily 35123bd2-3540-11e8-9fbf-001a4a160176 9116045 Whether other Krüppel-like zinc finger proteins might mediate the embryonic-to-fetal globin gene switch is a question of great interest. 8 MESH:D006863 activates IP:IPR000971 IP:IPR000971 Phenotype 811b56d6-352b-11e8-9192-001a4a160175 27825818 Further lowering of the pH reverses globin unfolding, suggesting that apo-Ngb folds back to a compact state. 8 PF:PF07508 activates IP:IPR000971 IP:IPR000971 ProteinFamily e42687a6-1af1-11f0-b759-0050569a791b 10.1016/j.biotechadv.2024.108421 Wallace et al. (2007)employed Cre recombinase-mediated genome replacement technique to substitute mouse globin regulatory domains with human synchronization regions, and further generated a precise mouse model of human thalassemia. 8 UNIPROT:P06730 activates IP:IPR000971 IP:IPR000971 Protein c13aaf72-cd5f-11e5-aade-001a4ae51247 7782349 ” Addition of bovine kidney eIF-4E to the m7GTP-Sepharose-treated lysates enhanced the rate of globin synthesis by about 1.8-fold (not shown). 8 UNIPROT:P12807 decreases IP:IPR000971 IP:IPR000971 Protein c7b984c2-bbe4-11e5-8abe-001a4ae51246 10.1016/j.ydbio.2006.08.010 While the inhibition of globin expression by A-MO was consistently observed, faint expression of globin persisted even at the higher level of injected A-MO in many embryos (for example,Fig. 7B). 8 UNIPROT:P12807 inhibits IP:IPR000971 IP:IPR000971 Protein c7b984c2-bbe4-11e5-8abe-001a4ae51246 10.1016/j.ydbio.2006.08.010 While 5 ng/blastomere of A-MO was sufficient to disrupt globin posteriorly, disruption of anterior globin expression was only observed at 10 ng/blastomere (Table 1;Figs. 8 MESH:D008024 increases IP:IPR000971 IP:IPR000971 Phenotype 1d599dfe-d9fa-11ee-9133-0050569a1f61 10.1182/blood.V92.4.1104 Assays of ligand-induced SKT6 cell hemoglobinization and globin expression. 8 UNIPROT:Q9UNA0 increases IP:IPR000971 IP:IPR000971 Protein c7b984c2-bbe4-11e5-8abe-001a4ae51246 10.1016/j.ydbio.2006.08.010 The effect of A-MO on VBI development was specifically due to the knockdown of ADMP2 as co-injection of ADMP2 Δ-5′ UTR RNA with A-MO rescued globin expression (Figs. 8 UNIPROT:Q4LE39 activates IP:IPR000971 IP:IPR000971 Protein 3c1b533a-374a-11e8-9fbf-001a4a160176 26142333 First, do all intermediaries of BCAA metabolism induce embryonic/fetal globin gene expression in EryD?|||We wanted to test whether BCAA intermediaries, as a class of compounds, act like the paradigmatic metabolic inducer of fetal hemoglobin, butyrate; the shared cellular and molecular effects would suggest a commonality of underlying molecular regulatory mechanism(s):First, do all intermediaries of BCAA metabolism induce embryonic/fetal globin gene expression in EryD? 8 UNIPROT:P01033 increases IP:IPR000971 IP:IPR000971 Protein e25235a2-bbff-11e5-9b9d-001a4ae51247 PMC1973161 The H-mutant, which lacks the H-region but retains the A-region and does not activate Stat5/3, could inhibit globin gene expression by Epo (Fig. 4C), indicating that the H-region and IL-2-induced Stat activity are dispensable for the inhibition activity.|||In contrast, the A-mutant, which lacks the A-region, failed to inhibit globin gene expression induced by Epo (Fig. 4C). 8 UNIPROT:P01033 decreases IP:IPR000971 IP:IPR000971 Protein 0afa5c14-2cbc-11f0-b759-0050569a791b 10.1182/blood.V98.13.3618 This result indicated that hGM-CSF, as well as EPO, induces adult globin expression, but suppresses embryonic globin expression in FL erythropoiesis of hGMR-Tg mouse embryo.|||On the other hand, embryonic globin expression was rather suppressed by EPO. 8 FPLX:BMP increases IP:IPR000971 IP:IPR000971 ProteinFamily 5db4e96a-da1f-11ee-9133-0050569a1f61 10.1016/S0925-4773(98)00070-7 Muscle actin gene expression was eliminated andα-T1 globin expression was restored in a dose-dependent manner by co-injection of any wildtype BMP.|||More directly, injection ofXenopusanimal caps with mRNAs encoding BMP-2 and BMP-4, or the BMP signal transducer, Smad1, induces globin expression (Jones et al., 1992;Maeno et al., 1994;Hemmati-Brivanlou and Thomsen, 1995;Graff et al., 1996;Thomsen, 1996). 8 UNIPROT:P60568 decreases IP:IPR000971 IP:IPR000971 Protein e25235a2-bbff-11e5-9b9d-001a4ae51247 PMC1973161 In addition, IL-2 inhibited Epo-induced globin gene expression (Fig. 4B).|||To examine whether IL-2 also inhibits Epo-induced globin gene expression, we transduced retroviral vector expressing mouse IL-2Rβ WT into EpoR-reconstituted Ba/F3. 8 MESH:D006427 increases IP:IPR000971 IP:IPR000971 Phenotype 20e2ee4e-c8e7-11e5-9624-001a4ae51246 PMC2190615 Hemin induction increased total amount of globin mRNA by approximately 2.5-fold, whereas the relative ratio between ε and γ genes remained unchanged.|||Hemin increases globin gene expression in K562 cells. 8 UNIPROT:Q2YIQ4 activates IP:IPR000971 IP:IPR000971 Protein 3c1b533a-374a-11e8-9fbf-001a4a160176 26142333 We wanted to test whether BCAA intermediaries, as a class of compounds, act like the paradigmatic metabolic inducer of fetal hemoglobin, butyrate; the shared cellular and molecular effects would suggest a commonality of underlying molecular regulatory mechanism(s):First, do all intermediaries of BCAA metabolism induce embryonic/fetal globin gene expression in EryD?|||First, do all intermediaries of BCAA metabolism induce embryonic/fetal globin gene expression in EryD? 7 IP:IPR000971 IP:IPR000971 increases IP:IPR000971 ProteinFamily 266bcfb8-c471-11e5-a92e-001a4ae51246 PMC2700329 In contrast, β globin did not allow expression of the α globin mutants R31S, H103Y, H103R, F117S, and P119S.|||This interpretation is further supported by the inability of β globin to enhance expression of α globin P119S inE coli. 7 IP:IPR000971 increases IP:IPR000971 IP:IPR000971 ProteinFamily 266bcfb8-c471-11e5-a92e-001a4ae51246 PMC2700329 In contrast, β globin did not allow expression of the α globin mutants R31S, H103Y, H103R, F117S, and P119S.|||This interpretation is further supported by the inability of β globin to enhance expression of α globin P119S inE coli. 7 CHEBI:30751 increases IP:IPR000971 IP:IPR000971 Chemical 44f4b242-c471-11e5-a92e-001a4ae51246 PMC2710936 SCFAs increase embryonic globin gene expression in murine fetal liver–derived EryD in vitro We reasoned that either SCFAs could not reactivate embryonic globin gene expression in murine fetal livers, or that SCFA concentrations achievable in vivo were insufficient, therefore we tested dose-dependent SCFA-responsiveness in fetal liver–derived EryD in vitro.|||We expect that eFLCs, as a robust, short-term, primary cell model, will offer distinct advantages for obtaining mechanistic insights into induction of embryonic/fetal globin gene expression by SCFAs, and perhaps other agents, in EryD in a physiologic setting.|||We found that elevated levels of SCFAs in utero modestly increased embryonic globin gene expression during primitive erythropoiesis in the yolk sac, but not during definitive erythropoiesis in the fetal liver.|||Results Endogenous elevations in SCFAs increase embryonic globin gene expression in the murine yolk sac, but not in the fetal liver Endogenous propionate levels were 2.5 and 3.6 μg/mL in plasma (0.033 and 0.067 mM, respectively) from 2 adult PCCA KO mice and undetectable in 2 non-PCCA KO mice.|||Discussion Here we show SCFAs induce the expression of embryonic/fetal β-type globin genes in EryD, a key therapeutic goal in β-globin gene disorders.|||SCFA-mediated up-regulation of globin gene expression in vitro was detectable in most cells and, in the absence of ins/EPO, affected primarily βH1in the murine andGγ in the human loci.Gγ, but notAγ, is up-regulated by hydroxyurea or butyrate in K562 cells.22,43Sangeman et al22described a cAMP-response element (CRE) at an ATF/CREB binding site in theGγ promoter, absent from theAγ promoter, through which butyrate acts in K562s. 7 UNIPROT:Q12800 increases IP:IPR000971 IP:IPR000971 Protein f59c8886-2be6-11f0-b759-0050569a791b 10.1016/S1016-8478(23)25235-8 The reduced level of CP2 suppresses the transcription of all globin genes expressed in MEL and K562 cells We have previously demonstrated that CP2 directly binds to and regulates the promoters of mouse α-and β-globin genes (Chaeet al., 1999;Kimet al., 1992).|||CP2 activates the expression of globin genes in an erythroid-cell specific manner To examine the importance of CP2 binding site within the globin promoter, we compared the activities of the mouse α-globin promoters with various factor binding sites mutations in K562 and 293T cells, as a model.|||Considering that CP2 regulates the expression of various types of globin genes (Fig. 1) in an erythroid-specific manner (Fig. 2), CP2 may interact with other erythroid restricted transcription factors or coactivators to enhance transcription of the globin genes.|||Discussion Here, we demonstrated that the reduced level of CP2 in K562 and MEL cells, a model of fetal and adult erythropoiesis, suppressed the expression of globin genes with the antisense CP2 expression method (Fig. 1). 6 IP:IPR000971 IP:IPR000971 activates MESH:D006863 Phenotype 35e4bb72-bc3c-11e5-ac4e-001a4ae51246 10.1016/j.jfoodeng.2012.05.042 These values indicate that all the globin gels produced at different pH in this study behave dilatantly (shear thickening).|||Microstructure Fig. 9shows the SEM images of decolorized globin gels produced at pH 2, 7 and 10.|||Particle size In order to determine how the particle size of gels is affected by pH, decolorized globin gels produced at pH 2, 7 and 10 were studied.Fig.|||This means that globin gels produced at pH 2 offered the greatest resistance to deformation.|||Globin gels produced at pH 2 were thus found to be more resistant to heat denaturation and subsequent aggregation than those produced at higher pH.|||However, globin gels produced at pH 7 showed the highest value ofG0, 6.284×103Pa, while for pH 2 and 10 the values obtained were 5.330×103and 3.031×103respectively, which could be due to the lower repulsion in the network at neutral pH. 6 UNIPROT:P17509 decreases IP:IPR000971 IP:IPR000971 Protein 52e1d422-ca00-11e5-ab20-001a4ae51246 15269212 HOXB6 Represses Globin mRNA Levels—We first confirmed our earlier findings that the HOXB6 protein repressed globin mRNA levels.|||HOXB6 and CBP Are Co-immunoprecipitated from K562 and Fetal Murine Liver Cells—Because HOXB6 can block CBPHAT activity, one possible mechanism for HOXB6 repression of globin gene expression would be by blocking CBP-HAT-mediated acetylation. 6 MESH:D006427 activates IP:IPR000971 IP:IPR000971 Phenotype 4e239d6a-cbf1-11e5-83a8-001a4ae51246 10082971 The earlier studies[12]showed that globin synthesis in intactb/breticulocytes was stimulated by exogenous hemin, but globin synthesis in control rat reticulocytes was inhibited by exogenous hemin.|||Addition of exogenous hemin stimulated globin synthesis in intactb/breticulocytes, but inhibited globin synthesis in normal reticulocytes[12]. 4 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:Q9H165 Protein 3c1b533a-374a-11e8-9fbf-001a4a160176 26142333 Therefore, we examined FL EryD for whether BCAA intermediaries that, like butyrate, induce fetal/embryonic β-type globin gene expression, also down-regulate BCL11A and SOX6, implying a common impact of these compounds on a shared β-globin regulatory network. 4 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P08047 Protein 757cf550-bc3d-11e5-8d2d-001a4ae51247 PMC1907364 RNase protection analysis (Figure 5(a)) and quantification using PhosphoImage and ImageQuant software showed that γ globin expression increased 6.8-fold and 4.3-fold following Sp1 and KLF8 knockdown, respectively (Figure 5(b)). 4 IP:IPR000971 IP:IPR000971 activates UNIPROT:P16410 Protein 9bfb3c6e-352b-11e8-9192-001a4a160175 27889340 The CD signal located at 250nm is caused by the globin portion. 4 IP:IPR000971 IP:IPR000971 increases UNIPROT:P40602 Protein 9aee47fe-3769-11e8-a51f-001a4a160176 9255936 250μM m7GpppGm inhibited globin mRNA primed transcription (Fig. 4, Lane D, dark bar), but stimulated ApG transcription approximately two-fold (Fig. 4, Lane D, light bar). 4 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P00540 Protein fce607ee-ab8d-11e6-9ac8-001a4ae51246 PMC4641806 Consistent with this, we find that markers of hematopoietic commitment (stem cell leukemia, scl) and differentiation (globin) are reduced at the neurula and tailbud stages, respectively, when ectodermal GATA2 expression is knocked down using antisense MOs (Dalgin et al., 2007) (Fig. S3). 4 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P22736 Protein d9df9cc4-1add-11f0-b759-0050569a791b 10.1016/j.jpsychires.2024.09.020 Ribosomal RNA and globin RNA was depleted using QIAseq FastSelect−rRNA HMR and −Globin kit (Qiagen, Germantown, MD). 4 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P35712 Protein 3c1b533a-374a-11e8-9fbf-001a4a160176 26142333 Therefore, we examined FL EryD for whether BCAA intermediaries that, like butyrate, induce fetal/embryonic β-type globin gene expression, also down-regulate BCL11A and SOX6, implying a common impact of these compounds on a shared β-globin regulatory network. 4 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:O95600 Protein 757cf550-bc3d-11e5-8d2d-001a4ae51247 PMC1907364 RNase protection analysis (Figure 5(a)) and quantification using PhosphoImage and ImageQuant software showed that γ globin expression increased 6.8-fold and 4.3-fold following Sp1 and KLF8 knockdown, respectively (Figure 5(b)). 4 IP:IPR000971 IP:IPR000971 activates UNIPROT:P69905 Protein be2bb6a0-e9fc-11ef-b449-0050569a791b 10.1016/j.cpcardiol.2024.102911 Thalassemia primarily involves mutations in the alpha or beta globin genes (Table 1), which disrupt the normal balance of globin chain synthesis.4,9In alpha-thalassemia, deletions or mutations in one or more of the four alpha-globin genes reduce the production of alpha-globin chains, while beta-thalassemia results from mutations in the beta-globin genes, leading to insufficient beta-globin chains. 4 IP:IPR000971 IP:IPR000971 activates MESH:D000755 Phenotype 1e369e28-04bc-11f0-ac21-0050569a1f61 10.1016/j.exphem.2024.104279 For example, the mutations that cause the production of diseased proteins or low amounts of ɑ globin or β globin that lead to sickle cell anemia or thalassemia could be rescued by using RNA modifications to restore protein production. 4 IP:IPR000971 IP:IPR000971 inhibits GO:0006351 Phenotype 2211b858-cc76-11e5-85cd-001a4ae51247 9332451 In order to investigate this possibility the stability of the hybrid globin-MT transcript was compared to the stability of the full globin transcript (Fig. 4) by arresting transcription with the addition of Actinomycin D and performing RNA extractions at certain time intervals (0, 3, 6 and 12 h) following this addition. 4 IP:IPR000971 IP:IPR000971 activates GO:0006351 Phenotype 9aee47fe-3769-11e8-a51f-001a4a160176 9255936 Similarly, T1 digested mRNA (at 50 nM) inhibited globin mRNA primed transcription (Fig. 4, Lane C, dark bar) and was able to stimulate transcription approximately twofold (Fig. 4, Lane C, light bar). 4 IP:IPR000971 IP:IPR000971 inhibits GO:0006351 Phenotype 295e2c5c-f298-11e5-96ee-001a4ae51247 15550029 HepG2 cell lines stably expressing the resultant β‐globin fusion transcripts from the respective reporter plasmids were treated with actinomycin D to arrest transcription. 4 IP:IPR000971 IP:IPR000971 activates MESH:D013789 Phenotype 1e369e28-04bc-11f0-ac21-0050569a1f61 10.1016/j.exphem.2024.104279 For example, the mutations that cause the production of diseased proteins or low amounts of ɑ globin or β globin that lead to sickle cell anemia or thalassemia could be rescued by using RNA modifications to restore protein production. 4 IP:IPR000971 IP:IPR000971 activates GO:0060756 Phenotype aaff095e-3aa6-11e8-87fd-001a4a160176 PMC5123917 For example, polymorphisms in the tyramine receptor TYRA-3, the neuropeptide Y receptor NPR-1, and the globin GLB-5 all cause population differences in foraging behavior and other chemosensory behaviors [32,34,35,36,37,38]. 4 IP:IPR000971 IP:IPR000971 activates MESH:D009569 Phenotype 2737ef4a-3403-11e8-a34b-001a4a160175 26544504 Interestingly, neuroglobin (Ngb), a six-coordinate globin that catalyzes the reduction of NO2−to NO, is shown to also be affected by mutations induced on the distal heme pocket, but for reasons different from that of Mb. 4 IP:IPR000971 IP:IPR000971 activates MESH:D000096 Phenotype fcef8b2c-f0f7-11ee-9aaa-0050569a1f61 10.1016/S0041-008X(03)00093-0 Globin was allowed to precipitate on ice for 30 min and then was centrifuged at 10,000gfor 10 min at 4°C and washed in 5 mL ice-cold acetone. 4 IP:IPR000971 IP:IPR000971 activates GO:0030154 Phenotype c6dc1c3e-351a-11e8-b868-001a4a160176 28642138 By inducing differentiation, the expression of adult-type globin genes (αAandβA) gradually increased, whereas that of embryonic-type globin genes (πandρ) did not change (Fig. 4A andFig. 4 IP:IPR000971 IP:IPR000971 activates GO:0034440 Phenotype 413ae106-055a-11f0-baad-0050569a1f61 10.1016/j.foodchem.2024.139111 However, it has also been observed that globin chains are necessary to access the lipid phase and induce lipid oxidation. 4 IP:IPR000971 IP:IPR000971 activates GO:0070527 Phenotype 74544942-2c51-11f0-bb75-0050569a1f61 10.1016/S0049-3848(02)00346-8 To our knowledge, this is the first report of globin-mediated inhibition of agonist-induced platelet aggregation by preventing the increase in intracellular calcium and release reaction. 4 IP:IPR000971 IP:IPR000971 activates GO:0030218 Phenotype c499e4f8-0c6b-11f0-b759-0050569a791b 10.1182/blood.V96.7.2606 Mildly anemic patients with homozygous HbCS (HbCS/CS) had increased hemolysis, which is perhaps pathophysiologically related to the extreme RBC rigidity.22The membrane accumulation of αCS, in addition to the excess β globin,22may have caused the ineffective erythropoiesis, as does αAaccumulation in severe β thalassemia (Table3).25,26The PITR, however, was increased to only 3 times the control value (Table2; PITR = 2.3). 4 IP:IPR000971 IP:IPR000971 activates GO:0042493 Phenotype c52d10f6-bc3f-11e5-ac4e-001a4ae51246 10.1016/S0378-1119(01)00858-7 Thus in combination with other HSs, DNA sequences upstream of HS3 increase the number of productive integration sites for establishing drug resistance driven by a globin gene promoter. 4 IP:IPR000971 IP:IPR000971 activates FPLX:DGC ProteinFamily 638ab7da-0515-11f0-ac21-0050569a1f61 10.1016/j.jinorgbio.2024.112638 While high resolution structures are still needed, these studies highlight important residues in the globin and middle domains that alter protein conformation and modulate DGC activity, which could affectc-di-GMP related phenotypes, such as biofilm formation. 4 IP:IPR000971 IP:IPR000971 inhibits FPLX:BMP ProteinFamily ea7055e0-ccfb-11e5-aade-001a4ae51247 8653784 If ectopic expression of Xmad1 requires endogenous BMP activity to induce globin, then the truncated BMP receptor may eliminate globin expression by blocking endogenous BMP signaling. 4 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily 6ab76a56-bbfc-11e5-9b9d-001a4ae51247 10.1016/j.pep.2004.08.014 coli.Although globin can accept heme before it is released from the ribosome in eukaryotic systems, it is still unclear whether this occurs in bacteria[17,18]and without heme, globins may adopt folding intermediate conformations whose stability depends on the temperature[10]. 4 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily 029b498c-352c-11e8-9fbf-001a4a160176 27341620 The color of cooked meat mainly depends on the heat-induced denaturation of myoglobin, and denaturation of the globin increases the susceptibility of heme to oxidation. 4 IP:IPR000971 IP:IPR000971 inhibits IP:IPR000971 ProteinFamily 0831b182-bbf9-11e5-9b9d-001a4ae51247 10.1016/S1079-9796(03)00024-X Increased amounts of TSA caused increased levels of β globin expression and reactivated the developmentally silenced γ globin gene in post-switch hybrids. 4 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 57b7fc18-f050-11ee-b22c-0050569a1f61 10.1016/S0002-9343(03)00447-9 In some instances, the mutant protein participates less directly in cellular pathology, such as in sickle cell anemia where a variant globin causes hemoglobin to polymerize under low oxygen tension, thereby damaging red blood cells. 4 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 27153938-3ab5-11e8-a51f-001a4a160176 10837653 An example of the latter is sickle cell anemia, where a variant globin molecule causes hemoglobin to undergo abnormal polymerization under low oxygen tension, leading to the destruction of distorted red blood cells. 4 IP:IPR000971 IP:IPR000971 activates MESH:D017086 Phenotype 71a890c6-0da8-11f0-b40b-0050569a1f61 10.1016/S1050-3862(98)00016-3 DOL assay In this example, genomic DNA samples collected from Sardinia were tested for a beta globin mutation that causes beta thalassemia in that population[17].|||In this example, genomic DNA samples collected from Sardinia were tested for a beta globin mutation that causes beta thalassemia in that population[17]. 4 IP:IPR000971 IP:IPR000971 activates MESH:D006461 Phenotype 2dae89e0-1be3-11f0-aa93-0050569a1f61 10.1016/j.blre.2023.101165 In patients with α-thalassemia, globin chain imbalance leads to ineffective erythropoiesis and hemolysis, resulting in chronic anemia, iron overload, and associated short- and long-term complications.|||•In patients with α-thalassemia, globin chain imbalance leads to ineffective erythropoiesis and hemolysis, resulting in chronic anemia, iron overload, and associated short- and long-term complications.|||Practice points •In patients with α-thalassemia, globin chain imbalance leads to ineffective erythropoiesis and hemolysis, resulting in chronic anemia, iron overload, and associated short- and long-term complications. 4 IP:IPR000971 IP:IPR000971 activates MESH:D000740 Phenotype 2dae89e0-1be3-11f0-aa93-0050569a1f61 10.1016/j.blre.2023.101165 In patients with α-thalassemia, globin chain imbalance leads to ineffective erythropoiesis and hemolysis, resulting in chronic anemia, iron overload, and associated short- and long-term complications.|||Practice points •In patients with α-thalassemia, globin chain imbalance leads to ineffective erythropoiesis and hemolysis, resulting in chronic anemia, iron overload, and associated short- and long-term complications.|||•In patients with α-thalassemia, globin chain imbalance leads to ineffective erythropoiesis and hemolysis, resulting in chronic anemia, iron overload, and associated short- and long-term complications. 4 IP:IPR000971 IP:IPR000971 activates GO:0030218 Phenotype 2dae89e0-1be3-11f0-aa93-0050569a1f61 10.1016/j.blre.2023.101165 In patients with α-thalassemia, globin chain imbalance leads to ineffective erythropoiesis and hemolysis, resulting in chronic anemia, iron overload, and associated short- and long-term complications.|||Practice points •In patients with α-thalassemia, globin chain imbalance leads to ineffective erythropoiesis and hemolysis, resulting in chronic anemia, iron overload, and associated short- and long-term complications.|||•In patients with α-thalassemia, globin chain imbalance leads to ineffective erythropoiesis and hemolysis, resulting in chronic anemia, iron overload, and associated short- and long-term complications. 4 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 1650f0b2-340a-11e8-a51f-001a4a160176 PMC5301825 Introduction Sickle cell trait (SCT) is caused by the inheritance of a single copy of the variant β globin gene, which results in production of abnormal sickle hemoglobin.|||Sickle cell trait (SCT) is caused by the inheritance of a single copy of the variant β globin gene, which results in production of abnormal sickle hemoglobin. 4 UNIPROT:Q99558 increases IP:IPR000971 IP:IPR000971 Protein f8a4591a-ccd1-11e5-b6ad-001a4ae51246 8858153 The results show that deletion of an individual HS from the LCR leads to severely reduced expression of the globin genes in some mouse lines. 4 UNIPROT:P08865 activates IP:IPR000971 IP:IPR000971 Protein 4e239d6a-cbf1-11e5-83a8-001a4ae51246 10082971 2; (2) the decrease in ‘free’ heme when biosynthesis is inhibited by SA; (3) the increase in this fraction when protein (and thus globin) synthesis is inhibited by cycloheximide, diminishing the substrate that reacts with heme in reaction 2 ofFig. 4 UNIPROT:P12643 activates IP:IPR000971 IP:IPR000971 Protein 5db4e96a-da1f-11ee-9133-0050569a1f61 10.1016/S0925-4773(98)00070-7 Note that BMP-2 and BMP-4 triggered a modest increase in the expression level of ventral mesodermal markers (Xhox3, Xcad3 and Xwnt8), above levels induced by activin alone, and BMP-2 cotreatment also induced globin at the tadpole stage (Fig. 2C). 4 UNIPROT:P21583 increases IP:IPR000971 IP:IPR000971 Protein 8a51b7c4-bbff-11e5-9b9d-001a4ae51247 10.1016/j.bbrc.2006.05.130 We observed that the simultaneous addition of dexamethasone and SCF (Kit-L) triggered a marked fetal globin gene expression when compared with the erythroid cultures grown in other two dexamethasone free differentiation media. 4 CHEBI:23965 activates IP:IPR000971 IP:IPR000971 Chemical 2267ec98-c9fe-11e5-b88f-001a4ae51247 15297311 Cycloheximide treatment, which blocked more than 95% of protein synthesis (not shown), completely inhibited estradiol-induced β major globin RNA up-regulation, indicating that additional downstream GATA-1 targets are required. 4 UNIPROT:Q13485 inhibits IP:IPR000971 IP:IPR000971 Protein 12ef69c4-c8de-11e5-a1fd-001a4ae51246 16908518 We next coexpressed the MOs with BMP4 and discovered that both Smad4α-MO and Smad4β-MO blocked the induction of globin by BMP4 (Fig. 4C,lanes 5-7). 4 UNIPROT:Q13485 decreases IP:IPR000971 IP:IPR000971 Protein 12ef69c4-c8de-11e5-a1fd-001a4ae51246 16908518 6C, both Smad4α-MO and Smad4β-MO greatly reduced the level of globin transcripts, suggesting that blood formation is sensitive to the levels of Smad4s. 4 UNIPROT:Q96CW6 inhibits IP:IPR000971 IP:IPR000971 Protein c6d5c326-3915-11e8-9192-001a4a160175 24036250 Wnt signaling is known to regulate blood development inXenopus[29], and the small molecule inhibitors XAV939 and IWR-1 did indeed reduce the size of the globin-expressing domain in the ventral region of embryo (Fig. 3). 4 UNIPROT:Q9FG35 decreases IP:IPR000971 IP:IPR000971 Protein c7b984c2-bbe4-11e5-8abe-001a4ae51246 10.1016/j.ydbio.2006.08.010 Globin expression, on the other hand, was eliminated by co-injection of tBR in all cases (Fig. 4A, lanes 3, 5 and 7 compared to lane 1), consistent with the fact that BMP signaling is essential for blood formation (Dale et al., 1992; Jones et al., 1992; Graff et al., 1994; Maeno et al., 1994a). 4 UNIPROT:Q13351 decreases IP:IPR000971 IP:IPR000971 Protein 95ad571a-c9fe-11e5-be63-001a4ae51246 15084587 Both the presence of the NF-E4 transgene and a dose reduction of EKLF increased the level of fetal globin expression at d12.5 in isolation. 4 FPLX:STAT5 decreases IP:IPR000971 IP:IPR000971 ProteinFamily 5eae8596-c8e0-11e5-9ad8-001a4ae51247 PMC1895518 One possibility is that alteration of STAT5 signaling disrupts globin expression indirectly caused by defects in normal axis formation or generation of ventral mesoderm. 4 PF:PF02985 activates IP:IPR000971 IP:IPR000971 ProteinFamily ca19409e-1b62-11f0-b759-0050569a791b 10.1016/j.psj.2024.103701 Heat treatment with high temperature, in addition to denaturation, usually causes the globin molecule to unfold, resulting in the formation of globin-hemichrome or ferrihemochrome, known as the dull brown pigment formed upon heating (Zhang and Wang, 2012;Roldán et al., 2013;Suman and Joseph, 2013). 4 UNIPROT:P40238 activates IP:IPR000971 IP:IPR000971 Protein e83c0d52-bc14-11e5-8abe-001a4ae51246 10.1016/S0925-4773(03)00176-X In a similar context,Cataldo et al. (1999)found increased levels of rat NAP1 in haematopoietic tissues, and up-regulation of the transcript in tissues cultured with megakaryocytopoietic ligand (Mpl), which has been shown to induce globin expression inXenopusembryo explants (Kakeda et al., 2002). 4 UNIPROT:Q4LE39 increases IP:IPR000971 IP:IPR000971 Protein 3c1b533a-374a-11e8-9fbf-001a4a160176 26142333 Therefore, we examined FL EryD for whether BCAA intermediaries that, like butyrate, induce fetal/embryonic β-type globin gene expression, also down-regulate BCL11A and SOX6, implying a common impact of these compounds on a shared β-globin regulatory network. 4 CHEBI:46024 inhibits IP:IPR000971 IP:IPR000971 Chemical 0831b182-bbf9-11e5-9b9d-001a4ae51247 10.1016/S1079-9796(03)00024-X Increased amounts of TSA caused increased levels of β globin expression and reactivated the developmentally silenced γ globin gene in post-switch hybrids. 4 CHEBI:46024 activates IP:IPR000971 IP:IPR000971 Chemical 0831b182-bbf9-11e5-9b9d-001a4ae51247 10.1016/S1079-9796(03)00024-X As shown inTable 2, TSA treatment between days 9 and 14 is able to upregulate γ globin production from 3.5% of total non-α globin to 11.6% at 30 nM, suggesting that the increase in TSA seen in the 14-day colonies was not a consequence of abnormal maturation of BFUe-derived colonies grown in the presence of trichostatin. 4 UNIPROT:P08246 increases IP:IPR000971 IP:IPR000971 Protein 844fb364-377f-11e8-b868-001a4a160176 10946210 HNE can also modulate the expression of various genes, such asc-mycand globin[78], procollagen type I[79], aldolase reductase[80,81],c-myb[82], and transforming growth factor β1[83]. 4 UNIPROT:Q9Y5W3 increases IP:IPR000971 IP:IPR000971 Protein e23dee70-4599-11f0-afc2-0050569a791b PMC9101247 Although KLF2 and KLF4 deficiency have been reported to impair embryonic β globin gene expression,45,46,47analysis of E10 EC MEKK3KO yolk sacs revealed no loss of globin gene expression (supplemental Figure 2D). 4 MESH:D004487 inhibits IP:IPR000971 IP:IPR000971 Phenotype 73bfb37c-390b-11e8-87fd-001a4a160176 25498503 The obvious cardiac abnormalities were noted when embryos developed to 48hpf, including un-consumed yolk sac, heart edema, reduced heart rate (HR) and less globin pigment. 4 MESH:D000242 inhibits IP:IPR000971 IP:IPR000971 Phenotype 7b489a34-0ca1-11f0-85c3-0050569a1f61 10.1016/S0925-4773(00)00304-X Our observation that cAMP or forskolin treatment inhibits the accumulation ofBh-1, embryonic globin, andtie1, which encodes an orphan receptor related to Tie2 that is required for blood vessel integrity, supports this hypothesis. 4 UNIPROT:Q9H165 inhibits IP:IPR000971 IP:IPR000971 Protein 3c1b533a-374a-11e8-9fbf-001a4a160176 26142333 In an unpublished work, we have found that butyrate down-regulates a number of key, recently characterized, fetal/embryonic globin gene repressors, including BCL11A and SOX6[44–48]. 4 CHEBI:62878 activates IP:IPR000971 IP:IPR000971 Chemical c6d5c326-3915-11e8-9192-001a4a160175 24036250 Wnt signaling is known to regulate blood development inXenopus[29], and the small molecule inhibitors XAV939 and IWR-1 did indeed reduce the size of the globin-expressing domain in the ventral region of embryo (Fig. 3). 4 UNIPROT:P01033 increases IP:IPR000971 IP:IPR000971 Protein 96714580-5c97-11e7-8c5f-001a4ae51246 PMC5235323 The results suggest that CVA induced gamma globin expression is enhanced by EPO (Fig. 5A). 4 UNIPROT:P01033 increases IP:IPR000971 IP:IPR000971 Protein 0afa5c14-2cbc-11f0-b759-0050569a791b 10.1182/blood.V98.13.3618 This result indicated that hGM-CSF, as well as EPO, induces adult globin expression, but suppresses embryonic globin expression in FL erythropoiesis of hGMR-Tg mouse embryo. 4 UNIPROT:P01033 decreases IP:IPR000971 IP:IPR000971 Protein e25235a2-bbff-11e5-9b9d-001a4ae51247 PMC1973161 These results showed that the A-region of IL-2Rβ is essential for IL-2-mediated inhibition of Epo-induced globin gene expression and suggest a potential role of signaling molecules activated through the A-region in IL-2-mediated inhibition of Epo-induced globin gene expression. 4 MESH:D012509 activates IP:IPR000971 IP:IPR000971 Phenotype e81d52ec-bc4e-11e5-9b9d-001a4ae51247 10.1016/S0303-7207(01)00744-4 The Rous sarcoma virus (RSV) promoter driving the Egr1 and globin cDNA's were previously described (Wolfe and Call, 1999). 4 UNIPROT:P08700 increases IP:IPR000971 IP:IPR000971 Protein e25235a2-bbff-11e5-9b9d-001a4ae51247 PMC1973161 Interestingly, EGF but not IL-3 stimulation induced expression of globin genes in BBLG expressing LG-Stat5 (Fig. 1D). 4 UNIPROT:Q12980 increases IP:IPR000971 IP:IPR000971 Protein 0788b244-bbf9-11e5-9b9d-001a4ae51247 10.1016/j.bcmd.2006.09.007 Hence the deletion of HS-4 to HS-40 abolished the expression of human α-like globin genes, even though the HS-48 remains intact. 4 PUBCHEM:455658 increases IP:IPR000971 IP:IPR000971 Chemical 5d94e654-bc07-11e5-9b9d-001a4ae51247 10.1016/j.bbaexp.2004.04.002 Furthermore, all three in vivo footprints changed character when the cells were treated with haemin, which is used to induce globin gene expression[46]. 4 UNIPROT:Q15937 activates IP:IPR000971 IP:IPR000971 Protein 5b51cb54-bbe0-11e5-8abe-001a4ae51246 10.1016/j.neurobiolaging.2006.03.003 Primers were designed to add uniqueNotI andBglII sites to the 5′ and 3′ ends of the PCR product which was then digested and ligated intoNotI/BglII-digested pT7APP751wtT90 to produce pT7βGb/APP751wtT90, which upon transcription produces a chimeric mRNA composed of the 5′-UTR and coding regions of globin fused to the entire 3′-UTR of APP mRNA followed by a 90 base polyadenylate tail. 4 FPLX:BMP activates IP:IPR000971 IP:IPR000971 ProteinFamily ea7055e0-ccfb-11e5-aade-001a4ae51247 8653784 If ectopic expression of Xmad1 requires endogenous BMP activity to induce globin, then the truncated BMP receptor may eliminate globin expression by blocking endogenous BMP signaling. 4 FPLX:BMP decreases IP:IPR000971 IP:IPR000971 ProteinFamily ea7055e0-ccfb-11e5-aade-001a4ae51247 8653784 If ectopic expression of Xmad1 requires endogenous BMP activity to induce globin, then the truncated BMP receptor may eliminate globin expression by blocking endogenous BMP signaling. 4 FPLX:BMP inhibits IP:IPR000971 IP:IPR000971 ProteinFamily ea7055e0-ccfb-11e5-aade-001a4ae51247 8653784 In contrast with this lack of effect on morphology and histology, the truncated BMP receptor does block the Xmad1-dependent induction of globin (Figure 6B). 4 UNIPROT:P01133 increases IP:IPR000971 IP:IPR000971 Protein e25235a2-bbff-11e5-9b9d-001a4ae51247 PMC1973161 Interestingly, EGF but not IL-3 stimulation induced expression of globin genes in BBLG expressing LG-Stat5 (Fig. 1D). 4 UNIPROT:P41250 increases IP:IPR000971 IP:IPR000971 Protein 5db4e96a-da1f-11ee-9133-0050569a1f61 10.1016/S0925-4773(98)00070-7 More directly, injection ofXenopusanimal caps with mRNAs encoding BMP-2 and BMP-4, or the BMP signal transducer, Smad1, induces globin expression (Jones et al., 1992;Maeno et al., 1994;Hemmati-Brivanlou and Thomsen, 1995;Graff et al., 1996;Thomsen, 1996). 4 MESH:D003513 decreases IP:IPR000971 IP:IPR000971 Phenotype 4e239d6a-cbf1-11e5-83a8-001a4ae51246 10082971 Since globin accounts for 95% of the protein in reticulocytes, cycloheximide will decrease the amount of available globin which should lead to an increase in heme. 4 MESH:D003513 inhibits IP:IPR000971 IP:IPR000971 Phenotype 4e239d6a-cbf1-11e5-83a8-001a4ae51246 10082971 Blood cells containing 13% reticulocytes from a+/+rat were incubated with a defined medium or the same medium containing 2 μM cycloheximide for 1 h at 37°C. Incorporation of3H-leucine into protein revealed that cycloheximide decreased globin synthesis to <5% of the control. 4 IP:IPR006361 activates IP:IPR000971 IP:IPR000971 ProteinFamily 4e239d6a-cbf1-11e5-83a8-001a4ae51246 10082971 2; (2) the decrease in ‘free’ heme when biosynthesis is inhibited by SA; (3) the increase in this fraction when protein (and thus globin) synthesis is inhibited by cycloheximide, diminishing the substrate that reacts with heme in reaction 2 ofFig. 4 UNIPROT:P10242 decreases IP:IPR000971 IP:IPR000971 Protein 8b6ed240-bbff-11e5-8abe-001a4ae51246 10.1016/j.bbrc.2006.03.203 Third, despite previous studies showing that globin gene expression is blocked by constitutive expression of c-Myb[29–31], the mechanism whereby c-Myb inhibits globin gene expression is not fully understood. 4 UNIPROT:Q9UBB5 inhibits IP:IPR000971 IP:IPR000971 Protein e4fca5ce-1bbf-11f0-a2ca-0050569a1f61 10.1016/j.jmb.2023.168343 Forced expression of an isolated ∼33-residue peptide of Mi-2α /CHD3 (a paralog of CHD4) relieves MBD2-mediated globin gene silencing and the expressed peptide interacts only with a subset of MBD2–NuRD complex components, which excludes native Mi-2α/CHD3.68We suspect that an analogous disruptive effect might result from expressing the corresponding CHD4 peptide to disrupt the CHD4-associated NuRD complex. 4 UNIPROT:P15009 increases IP:IPR000971 IP:IPR000971 Protein 0788b244-bbf9-11e5-9b9d-001a4ae51247 10.1016/j.bcmd.2006.09.007 Hence the deletion of HS-4 to HS-40 abolished the expression of human α-like globin genes, even though the HS-48 remains intact. 4 UNIPROT:P15009 inhibits IP:IPR000971 IP:IPR000971 Protein 8a57fa8c-bc52-11e5-8abe-001a4ae51246 10.1016/S0955-0674(02)00327-7 An alternative possibility is that HS4 might prevent the globin LCR enhancers from disrupting the adjacent 16-kb heterochromatin domain. 4 CHEBI:17968 activates IP:IPR000971 IP:IPR000971 Chemical 3c1b533a-374a-11e8-9fbf-001a4a160176 26142333 In an unpublished work, we have found that butyrate down-regulates a number of key, recently characterized, fetal/embryonic globin gene repressors, including BCL11A and SOX6[44–48]. 4 MESH:D008024 activates IP:IPR000971 IP:IPR000971 Phenotype e83c0d52-bc14-11e5-8abe-001a4ae51246 10.1016/S0925-4773(03)00176-X In a similar context,Cataldo et al. (1999)found increased levels of rat NAP1 in haematopoietic tissues, and up-regulation of the transcript in tissues cultured with megakaryocytopoietic ligand (Mpl), which has been shown to induce globin expression inXenopusembryo explants (Kakeda et al., 2002). 4 UNIPROT:P10721 increases IP:IPR000971 IP:IPR000971 Protein 67b62c8e-ca02-11e5-ab20-001a4ae51246 PMC1432098 Disruption of c-kit signaling in the entire marginal zone blocked expression of globin throughout the VBI in most embryos at stage 33 (n = 20 of 22;Figure 2G), whereas disruption of c-kit signaling in the ventral marginal zone blocked expression of globin only in the posterior VBI (n = 68 of 114;Figure 2H). 4 UNIPROT:Q99717 activates IP:IPR000971 IP:IPR000971 Protein a4b065a6-cbff-11e5-a19a-001a4ae51247 9753318 Similarly, the presence of the mutant Smad3 had no effect on the Smad5 induction of globin (Figure 3D). 4 UNIPROT:P12644 activates IP:IPR000971 IP:IPR000971 Protein e1fc5cd6-d9f1-11ee-b346-0050569a791b 10.1016/S0925-4773(98)00139-7 With equimolar cerberus and BMP4, expression of markers induced exclusively by cerberus (Otx-2, NCAM, Nkx2.5, Nkx2.3, CG13, Edd) and those induced exclusively by BMP4 (T4 globin, XeHAND) were reduced, indicative of mutual antagonism. 4 IP:IPR000971 inhibits IP:IPR000971 IP:IPR000971 ProteinFamily 0831b182-bbf9-11e5-9b9d-001a4ae51247 10.1016/S1079-9796(03)00024-X Increased amounts of TSA caused increased levels of β globin expression and reactivated the developmentally silenced γ globin gene in post-switch hybrids. 4 MESH:D006427 activates IP:IPR000971 IP:IPR000971 Phenotype 20e2ee4e-c8e7-11e5-9624-001a4ae51246 PMC2190615 These results suggest that the hemin-induced globin gene activation in K562 cells involves a mechanism other than histone acetylation. 4 MESH:D006427 activates IP:IPR000971 IP:IPR000971 Phenotype 51d0c520-bc31-11e5-9b9d-001a4ae51247 10.1016/S0003-9861(03)00089-4 These results indicate that CN–hemin addition alone to newly synthesized globin chains may not be sufficient to allow complete folding and generation of stabilized chains which are able to migrate on CAE-like purified globin chains. 4 UNIPROT:O43474 increases IP:IPR000971 IP:IPR000971 Protein e23dee70-4599-11f0-afc2-0050569a791b PMC9101247 Although KLF2 and KLF4 deficiency have been reported to impair embryonic β globin gene expression,45,46,47analysis of E10 EC MEKK3KO yolk sacs revealed no loss of globin gene expression (supplemental Figure 2D). 4 CHEBI:68481 activates IP:IPR000971 IP:IPR000971 Chemical eb73bf74-c46b-11e5-85e4-001a4ae51246 24685370 mTOR inhibitors may cause early differentiation of the erythroid precursors and reduced globin synthesis[94]. 4 UNIPROT:Q01826 activates IP:IPR000971 IP:IPR000971 Protein 3517a260-c9ff-11e5-9b70-001a4ae51247 15618465 SATB1 increases embryonic globin production To investigate the influence of SATB1 onglobingene regulation, a SATB1 expression vector was stably transfected into K562 cells that endogenously express a low level (compared with T lymphocytes) of SATB1 (or its isoform),14,27to generate K562/SATB1. 4 MESH:D005576 inhibits IP:IPR000971 IP:IPR000971 Phenotype 7b489a34-0ca1-11f0-85c3-0050569a1f61 10.1016/S0925-4773(00)00304-X Our observation that cAMP or forskolin treatment inhibits the accumulation ofBh-1, embryonic globin, andtie1, which encodes an orphan receptor related to Tie2 that is required for blood vessel integrity, supports this hypothesis. 4 UNIPROT:Q86UQ8 increases IP:IPR000971 IP:IPR000971 Protein 95ad571a-c9fe-11e5-be63-001a4ae51246 15084587 Both the presence of the NF-E4 transgene and a dose reduction of EKLF increased the level of fetal globin expression at d12.5 in isolation. 4 UNIPROT:P03702 activates IP:IPR000971 IP:IPR000971 Protein 1dc464c2-c9ff-11e5-9b70-001a4ae51247 15367428 The divergent changes in the absolute levels of gamma- and beta-globin mRNA on culture day 8 (Figure 6A-B) caused profound changes in the gamma/total globin ratio from 1.4 ± 3.2% in EPO to 61.5 ± 30.7% in EST (Figure 6D). 4 UNIPROT:Q9BQI3 inhibits IP:IPR000971 IP:IPR000971 Protein c7fb550c-8649-11f0-86f5-0050569a1f61 PMC7948285 HRI is inhibited when heme levels increase, allowing globin synthesis. 4 MESH:D004121 decreases IP:IPR000971 IP:IPR000971 Phenotype 96448888-cb2a-11e5-9aa0-001a4ae51247 12446462 Treatment with DMSO induced α- and β-globin mRNA after 4 days of culture in both 745A/Neo and 745A/Bcl-XLAS cells, indicating that inhibition of Bcl-XLin MEL cells did not prevent expression of globin. 4 UNIPROT:P61006 increases IP:IPR000971 IP:IPR000971 Protein 96448888-cb2a-11e5-9aa0-001a4ae51247 12446462 Treatment with DMSO induced α- and β-globin mRNA after 4 days of culture in both 745A/Neo and 745A/Bcl-XLAS cells, indicating that inhibition of Bcl-XLin MEL cells did not prevent expression of globin. 4 MESH:D013963 increases IP:IPR000971 IP:IPR000971 Phenotype 790eb50c-8e5d-11e7-82ff-001a4ae51246 PMC5490074 This pathway appears to be conserved from zebrafish to humans, as a thyroid hormone antagonist induces fetal globin expression in adult zebrafish, and conversely, thyroid hormone treatment of human fetal CD34+ cells increases adult globin expression. 4 MESH:D013739 activates IP:IPR000971 IP:IPR000971 Phenotype 68a12b12-3783-11e8-8f56-001a4a160175 11343670 Testosterone also enhances the production of heme and globin(94–96). 4 UNIPROT:P35712 inhibits IP:IPR000971 IP:IPR000971 Protein 3c1b533a-374a-11e8-9fbf-001a4a160176 26142333 In an unpublished work, we have found that butyrate down-regulates a number of key, recently characterized, fetal/embryonic globin gene repressors, including BCL11A and SOX6[44–48]. 4 UNIPROT:Q96E09 inhibits IP:IPR000971 IP:IPR000971 Protein 386e3000-dbbd-11ea-84da-001a4a160176 PMC7486200 Intriguingly, the results showed that FAM122A knockdown significantly increased various globin protein and/or gene expressions (Figures 2A and 2B), and enhanced the percentages of CD71+/GPA+and GPA+/Band3+cells (Figures 2C and 2D) and DAB+cells (Figure 2E). 4 UNIPROT:Q96E09 decreases IP:IPR000971 IP:IPR000971 Protein 386e3000-dbbd-11ea-84da-001a4a160176 PMC7486200 Notably, FAM122A knockout itself could promote the expressions of globin genes and HbG protein, and increased DAB+cells, indicating that FAM122A deletion may spontaneously trigger or be prone to erythroid differentiation. 4 MESH:D008942 inhibits IP:IPR000971 IP:IPR000971 Phenotype 9cf3cc44-052b-11f0-bb39-0050569a791b 10.1182/bloodadvances.2024012679 Autophagy plays a key role in the degradation of excess free globin chains and mitochondrial clearance (mitophagy) to support effective maturation of RBCs.27-30Using transmission electron microscopy analysis of reticulocytes, we see that mitoxantrone decreases globin precipitates inHbbTh3/+mice (Figure 4A), consitent with the results of triton-acetic acid-urea gel analysis (Figure 3E-F). 4 FPLX:AKT increases IP:IPR000971 IP:IPR000971 ProteinFamily 6b99d8ac-3916-11e8-9fbf-001a4a160176 24095799 Induction of Akt in HEL cells caused the transcript levels of EPOR, JunB and ζ Globin to fall below the limits of detection by qRT-PCR. 4 UNIPROT:P35555 activates IP:IPR000971 IP:IPR000971 Protein 1e369e28-04bc-11f0-ac21-0050569a1f61 10.1016/j.exphem.2024.104279 SGs are induced during the early stages of erythropoiesis and help coordinate globin RNA translation and heme production [99]. 4 UNIPROT:P68871 activates IP:IPR000971 IP:IPR000971 Protein 1dc464c2-c9ff-11e5-9b70-001a4ae51247 15367428 The divergent changes in the absolute levels of gamma- and beta-globin mRNA on culture day 8 (Figure 6A-B) caused profound changes in the gamma/total globin ratio from 1.4 ± 3.2% in EPO to 61.5 ± 30.7% in EST (Figure 6D). 4 UNIPROT:Q16621 increases IP:IPR000971 IP:IPR000971 Protein 3a43ea60-ca5d-11e5-a3f7-001a4ae51246 12920035 Of these, Nfe2 is the most abundant AP1/NFE2 binding activity in fetal liver cells.50To test the hypothesis that p45Nfe2 activates globin gene expression through these sites, we used a genetic approach in mice (Figure 5). 4 UNIPROT:Q13485 increases IP:IPR000971 IP:IPR000971 Protein 12ef69c4-c8de-11e5-a1fd-001a4ae51246 16908518 Smad10 induced neural markers directly in the absence of mesoderm when expressed at high levels; whereas Smad4β induced globin expression and ventralized mesodermal induction.|||Unlike Smad10, Smad4β did not induce neural markers, but instead stimulated the expression of globin (Fig. 2B). 4 UNIPROT:P08729 increases IP:IPR000971 IP:IPR000971 Protein d5cc4ad8-ca01-11e5-ab20-001a4ae51246 15811954 Replacement of SCL in the VBI of xNAP1L-depleted embryos restores α-globin expression SCL is the earliest component of the hematopoietic transcriptional network known to be affected by xNAP1L depletion.43To test whether the effect on SCL was potentially the cause of subsequent hematopoietic failure, we attempted to rescue globin mRNA levels in xNAP1L morphant embryos by SCL expression.|||SCL is the earliest component of the hematopoietic transcriptional network known to be affected by xNAP1L depletion.43To test whether the effect on SCL was potentially the cause of subsequent hematopoietic failure, we attempted to rescue globin mRNA levels in xNAP1L morphant embryos by SCL expression. 4 UNIPROT:Q9BQI3 inhibits IP:IPR000971 IP:IPR000971 Protein 333aea78-c8de-11e5-9cb8-001a4ae51247 PMC1852217 As discussed, the essential protective role of HRI in these 3 anemias is achieved by activation of the HRI/eIF2αP signaling pathway to inhibit globin synthesis (Figure 1–2).|||Recently, we have found that this translational regulation of HRI is essential to reduce excessive synthesis of globin proteins and phenotypic severities in the anemias of iron deficiency,5erythropoietic protoporphyria, and β-thalassemia.6Most significantly, HRI is responsible for the morphologic hypochromia and microcytosis of these 3 anemias. 4 UNIPROT:Q5VYS8 increases IP:IPR000971 IP:IPR000971 Protein 08c5621a-bbf9-11e5-9b9d-001a4ae51247 10.1016/j.bcmd.2003.07.001 HS2 can enhance expression of β-like globin gene both transiently from integrated constructs and after integration into a chromosome in transfected erythroid cell lines[22,23].|||Previous studies have shown that HS2 appeared to be equally active at the embryonic, fetal, and adult stages[31,32], and HS2 can enhance expression of β-like globin genes both transiently and after stable integration into chromosome DNA[22,23]. 3 IP:IPR000971 IP:IPR000971 activates MESH:D019190 Phenotype 2dae89e0-1be3-11f0-aa93-0050569a1f61 10.1016/j.blre.2023.101165 In patients with α-thalassemia, globin chain imbalance leads to ineffective erythropoiesis and hemolysis, resulting in chronic anemia, iron overload, and associated short- and long-term complications.|||Practice points •In patients with α-thalassemia, globin chain imbalance leads to ineffective erythropoiesis and hemolysis, resulting in chronic anemia, iron overload, and associated short- and long-term complications. 3 IP:IPR000971 IP:IPR000971 activates IP:IPR000971 ProteinFamily 266bcfb8-c471-11e5-a92e-001a4ae51246 PMC2700329 Coexpression of β globin enhances production of WT α globin inE coli.21Coexpressed β globin also enhanced the production of K99E, K99N, and A130 D α globins (Figure 5C).|||However, α globin synthesis is significantly enhanced by coexpression of either AHSP or β globin (Figure 5B lanes 2 and 4). 3 IP:IPR000971 IP:IPR000971 inhibits PF:PF00292 ProteinFamily d6ffe598-bc34-11e5-ac4e-001a4ae51246 PMC2714456 From a biological perspective, the globin depleted PAX gene versus the PBMC difference expression profile provides a window into real time erythrocyte expression profiles in sickle cell disease.|||From a biological perspective, the globin depleted PAX gene versus the PBMC difference expression profile provided a window into real time erythrocyte expression profiles in vascular diseases In clinical investigations on hematological diseases such as sickle cell anemia, thalassemia, G6PD, pyruvate kinase deficiency and in malaria where the early red blood cell progenitors represent major contributors to pathophysiology, insights into the transcription profile of these cells may contribute greatly to our understanding of mechanism of disease, prognosis, and responses to therapeutics.|||Further analysis on the 106 probe sets showed a reasonably high correlation to the PBMCs from the current study with a correlation coefficient value of 0.51, followed by globin reduced PAX with a correlation coefficient value of 0.41. 3 FPLX:Activin activates IP:IPR000971 IP:IPR000971 ProteinFamily 6c1f8372-cc75-11e5-b6ad-001a4ae51246 PMC1170341 This XFKH1–globin gene (−2850I‐globin) was strongly induced by activin in this assay (Figure 1B, compare lanes 1 and 2).|||The fusion gene I‐102‐globin was strongly induced by activin, at least as efficiently as −102I‐globin, which contains the intron in its natural context (Figure 4, compare lanes 1, 2, 5 and 6). 3 PUBCHEM:53477764 inhibits IP:IPR000971 IP:IPR000971 Chemical a9840a58-c825-11ee-9aaa-0050569a1f61 10.1016/j.ttbdis.2023.102170 Preparation and quality control of haem-depleted globin Haem-depleted globin was prepared according to the original publication (Ascoli et al., 1981).|||Haemoglobin solution was added drop-wise into swirling acidic acetone to extract haem and precipitate haem-depleted globin. 3 UNIPROT:Q9H165 increases IP:IPR000971 IP:IPR000971 Protein c1af84ae-c473-11e5-9da3-001a4ae51247 PMC4475914 "Notably, decrease of BCL11A gene expression upon compound II treatment does not decrease the level of β globin gene expression (Fig. 5), which is consistent with a previous report that the promoter activity of the β globin gene remains unchanged in cells with RNAi-mediated knockdown of BCL11A (32).|||Regarding the NaB effect, downregulation of BCL11A by RNA interference (RNAi) (20) or NaB (42) was shown to elevate the level of γ globin mRNA." 3 IP:IPR000971 activates IP:IPR000971 IP:IPR000971 ProteinFamily 266bcfb8-c471-11e5-a92e-001a4ae51246 PMC2700329 Coexpression of β globin enhances production of WT α globin inE coli.21Coexpressed β globin also enhanced the production of K99E, K99N, and A130 D α globins (Figure 5C).|||However, α globin synthesis is significantly enhanced by coexpression of either AHSP or β globin (Figure 5B lanes 2 and 4). 3 CHEBI:30751 activates IP:IPR000971 IP:IPR000971 Chemical 44f4b242-c471-11e5-a92e-001a4ae51246 PMC2710936 SCFAs induce embryonic globin genes in the majority of erythroid cells, with BIE-treated eFLCs having detectable βH1-globin gene expression in 11 of 15 individual eFLCs, compared with 0 of 15 individual eFLCs cultured in ins/EPO.|||This finding implied that embryonic globin genes could be induced in primary EryD by SCFAs alone.|||However, SCFAs at higher concentrations did up-regulate embryonic globin, or human transgenic γ-globin, gene expression in murine EryD in vitro. 3 UNIPROT:Q05D32 increases IP:IPR000971 IP:IPR000971 Protein aabf7a8e-bc39-11e5-8abe-001a4ae51246 PMC2964535 In this study, we show that overexpression of CTDSPL2 significantly increased the ε- and γ- globin gene expression in K562 cells and CD34+ cells derived from UCB while have faint effect on ζ-, α- and β-globin gene.|||CTDSPL2 overexpression increases ε- and γ- globin gene expression in CD34+ HPCs derived from UCB Two high titer lentiviruses that carry pWPXL-CTDSPL2 and pLVTHM-CTDSPL2 RNAi were obtained.|||Repression of the CTDSPL2 gene decreased the transcription of the globin genes, especially the ε-globin gene. 2 IP:IPR000971 IP:IPR000971 increases UNIPROT:P16581 Protein 5514f792-bc31-11e5-8d2d-001a4ae51247 10.1016/j.abb.2005.02.006 MetHb, the precursor of globin, was shown to cause elevation of E-selectin expression of endothelial cells[53]. 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q13351 Protein cf104898-2d1b-11f0-b759-0050569a791b 10.1182/blood.V97.6.1861 EKLF and globin gene regulation Activation of EKLF resulted in a dramatic activation of the human β-globin gene in the cell lines we used, confirming the critical role of EKLF in β-globin gene expression. 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q13351 Protein b167f8ba-bbf4-11e5-9b9d-001a4ae51247 PMC1892846 Altered transcriptional regulation of the endogenous β-like globin genes in MEL cells Discrepancies between the ability of artificial transcription factors to activate naked reporter DNA as opposed to an endogenous chromosome locus has been reported previously[44], leading us to study the effects of modified EKLF on an endogenous β-globin locus during erythroid differentiation in MEL cells. 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:P06315 Protein 4ce0b2fe-bbf6-11e5-8abe-001a4ae51246 10.1016/j.cbpb.2006.11.002 Globin sequences PCR products of the A2, A1, and B2 globin chains, after cloning, yielded only one sequence for each chain type with high similarity to published sequences of the respective chains fromR. 2 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P81172 Protein 7807f8c8-c46d-11e5-91a7-001a4ae51247 PMC4321326 Individuals carrying β-thalassemia trait have a mild globin chain imbalance and ineffective erythropoiesis,37resulting in increased erythroid activity accompanied by a variable but usually mild microcytic anemia,20associated with a mild increase in Epo.38Our data show that β-thalassemia carriers have suppressed hepcidin concentrations overall and out of proportion to their iron stores. 2 IP:IPR000971 IP:IPR000971 decreases UNIPROT:P01308 Protein cc4fa246-3388-11e8-bf76-001a4a160175 24973725 The results of the present study indicate that the globin part of hemoglobin causes the loss of insulin since insulin degraded in the presence of purified globin to a similar extent than with hemoglobin. 2 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P49675 Protein e3b76e44-ab8c-11e6-9ac8-001a4ae51246 PMC4646363 Together, the results suggest a mechanism for globin-catalyzed STAR reduction (Scheme 1) in which ferric heme is reduced by 1e− (Reaction 1), ferrous heme transiently interacts with STAR (Reaction 2), reduces STAR to sulfite (Reaction 3), and releases sulfite (Reaction 4). 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q9H165 Protein 1c77309c-8749-11f0-afc2-0050569a791b 10.1016/j.genrep.2020.100934 On the 21st day of erythroid differentiation, gamma globin gene switching was prevented using BCL11a specific siRNA by electroporation. 2 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P20382 Protein 333aea78-c8de-11e5-9cb8-001a4ae51247 PMC1852217 The hallmarks of HRI deficiency in these 3 anemias are increased globin inclusions, decreased red blood cell number with normal MCV and MCH, and aggravation of ineffective erythropoiesis. 2 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:O00767 Protein 3487b6e6-3406-11e8-9fbf-001a4a160176 PMC5659067 The question of what percentage of donor chimerism is necessary to cure SCD is critical in identifying the target percentage of the transferred globin gene needed to reverse SCD. 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:O00767 Protein 8007cdaa-cc70-11ee-ae05-0050569a1f61 10.1016/j.paed.2015.03.003 Some other beta globin variants (HbC, DPunjab, OArab) interact as compound heterozygotes with HbS to produce SCD of variable severity, and HbS also interacts with beta thalassaemia and other thalassaemic mutations (e.g. 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:O00767 Protein e4411476-3904-11e8-a34b-001a4a160175 28735981 Sickle-cell disease (SCD) is caused by an autosomal recessive mutation of theHBB(beta globin) gene leading to abnormality of β-globin chain, hemoglobin S (HbS), which polymerizes when deoxygenated, resulting in deformed and rigid erythrocytes. 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q8MQW8 Protein a6cf592c-38ff-11e8-8636-001a4a160175 26264264 More recently (2011), Spoto's group reported the attomolar detection of unamplified human β globin gene fragments, extracted from blood cells, by the development of a NPs-enhanced SPRi based on peptide nucleic acids (PNAs) sensor, coupling the high selectivity of PNAs probe to the amplification features offered by AuNSPs (20±5nm in diameter). 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:P10995 Protein 7b8ca942-3754-11e8-a51f-001a4a160176 25679069 Between 6 and 8 wk of gestation there is a switch leading to expression of the alpha and the gamma globin genes, that produces the fetal hemoglobin – HbF (alpha-2, gamma-2). 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q16769 Protein 5514f792-bc31-11e5-8d2d-001a4ae51247 10.1016/j.abb.2005.02.006 While hemin damage is counteracted by the induced HO-1, globin mediated EC damage by β-chain globin is still effective. 2 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P10242 Protein 8b6ed240-bbff-11e5-8abe-001a4ae51246 10.1016/j.bbrc.2006.03.203 Or, since the induction of β-like globin genes is inhibited in both K562 cells and MEL cells that constitutively express c-Myb[30,37], c-Myb may act on regulatory elements in the LCR. 2 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P15976 Protein 70cd99ae-c8e7-11e5-a1fd-001a4ae51246 18063753 The biologic consequences of elevated Hls5 in erythroid cells, viz severely impaired globin synthesis and restricted cell growth (Figure 1F-I), are consistent with Hls5 inhibiting the activity of GATA-1, because GATA-1 regulates globin gene transcription and cell cycle progression.15,16Hls5 might, therefore, play an important role in the maturation of red blood cells by modulating GATA-1 activity and expression of lineage-restricted functional genes.9,12–14,17The presence of numerous GATA binding sites in the Hls5 promoter,4adds another potential layer of cross-regulation between these molecules. 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:P15976 Protein 70cd99ae-c8e7-11e5-a1fd-001a4ae51246 18063753 The biologic consequences of elevated Hls5 in erythroid cells, viz severely impaired globin synthesis and restricted cell growth (Figure 1F-I), are consistent with Hls5 inhibiting the activity of GATA-1, because GATA-1 regulates globin gene transcription and cell cycle progression.15,16Hls5 might, therefore, play an important role in the maturation of red blood cells by modulating GATA-1 activity and expression of lineage-restricted functional genes.9,12–14,17The presence of numerous GATA binding sites in the Hls5 promoter,4adds another potential layer of cross-regulation between these molecules. 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q5VYS8 Protein 8cef2d52-bc3d-11e5-9b9d-001a4ae51247 10.1016/j.jmb.2005.05.039 Similarly, HS2 transcription in the integrated plasmids and the endogenous genome may result from direct loop formation between the HS2 enhancer and thecis-linked globin promoter, which then initiates transcription in the HS2 enhancer. 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:O14901 Protein 3b2e6234-ca5d-11e5-9088-001a4ae51247 12920040 EKLF-related transcription factors, such as basic KLF (BKLF) and embryonic/fetal 3-like globin gene-activating KLF (FKLF) 1 and 2,22-24play as-yet-undefined roles during normal development. 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:P69905 Protein 92c729da-bbea-11e5-9b9d-001a4ae51247 10.1016/j.meegid.2005.08.001 During gestation, production is shifted to both alpha-1 and alpha-2 globin, which are the main producers of alpha-globin throughout adult life (Higgs et al., 1989). 2 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q811S7 Protein 267478b6-cb8d-11e5-9498-001a4ae51246 10995745 Studies of human globin chain synthesis in NF2d9 nullizygous mice will address this question. 2 IP:IPR000971 IP:IPR000971 increases PUBCHEM:53477764 Chemical fd5c3924-ca00-11e5-ab20-001a4ae51246 15863440 With this model in mind, the consequences of haemoglobin S instability became clear to biochemists during the 1980s (Fig. 2).35–3875Impaired stability of the globin leads to accelerated breakdown of the molecule, releasing large quantities of toxic iron and haem compounds into the cell. 2 IP:IPR000971 IP:IPR000971 activates CHEBI:17245 Chemical 82a2080e-45ce-11f0-afc2-0050569a791b 10.1016/j.envres.2021.112523 Red blood cells are destroyed to produce globin and heme, which produce biliverdin (a precursor of bilirubin) and CO under the action of heme oxygenase. 2 IP:IPR000971 IP:IPR000971 activates CHEBI:33709 Chemical 72ac6130-3409-11e8-bf76-001a4a160175 25721910 Hb-Hope is another less common beta globin chain variant which arises due to a point mutation in position 136, causing an amino acid change from glycine to aspartic acid. 2 IP:IPR000971 IP:IPR000971 inhibits MESH:D003221 Phenotype 772bdd82-2ce8-11f0-a2ca-0050569a1f61 10.1182/blood.V98.3.554 Red and green fluorophores were found unsuitable to label intracytoplasmic globins because in a significant proportion of cases it was difficult to distinguish between stained and unstained cells; another problem is that these colors are also commonly used to label FISH probes.2Using AMCA to label the globin eliminated this source of confusion. 2 IP:IPR000971 IP:IPR000971 activates GO:0010467 Phenotype 0831b182-bbf9-11e5-9b9d-001a4ae51247 10.1016/S1079-9796(03)00024-X Induction of γ globin in BFUe colonies To test whether TSA can induce γ gene expression in primary erythroid cells, peripheral blood mononuclear cells from a normal adult were isolated and cultured in the presence or absence of TSA under conditions allowing optimal maturation in methylcellulose. 2 IP:IPR000971 IP:IPR000971 activates GO:0006351 Phenotype 5a3dad80-2ccb-11f0-bb75-0050569a1f61 10.1182/blood.V98.9.2664 This results in low expression of intron-dependent genes, such as globin.9,10Introns in the globin gene enhance transcription and allow proper 3′ end processing and export of globin transcripts into the cytoplasm.11–14Retention of introns of the globin genes can be achieved by using vectors that contain the globin gene in reverse orientation to the viral transcriptional unit. 2 IP:IPR000971 IP:IPR000971 activates GO:0006351 Phenotype 43186f4e-135f-11f0-b40b-0050569a1f61 10.1182/blood.V87.11.4552.bloodjournal87114552 MafK, and activate transcription of the target genes, as in the case for erythroid cells, globin genes.32However, the target gene(s) of NF-E2 p45 remains to be identified in the megakaryocytic lineage. 2 IP:IPR000971 IP:IPR000971 activates GO:0006351 Phenotype 8cef2d52-bc3d-11e5-9b9d-001a4ae51247 10.1016/j.jmb.2005.05.039 Similarly, HS2 transcription in the integrated plasmids and the endogenous genome may result from direct loop formation between the HS2 enhancer and thecis-linked globin promoter, which then initiates transcription in the HS2 enhancer. 2 IP:IPR000971 IP:IPR000971 activates GO:0006351 Phenotype 4262a9e2-e854-11e5-926d-001a4ae51247 10.1074/jbc.272.42.26585 There is evidence that globin enhancers activate gene transcription by increasing the number of expressing cells rather than the level of transcription in expressing cells (61-63). 2 IP:IPR000971 IP:IPR000971 inhibits GO:0009058 Phenotype 539f1bf0-2c88-11f0-b759-0050569a791b 10.1182/blood.V99.10.3505 Using gel mobility shift assays in K562 erythroleukemic cells, Broyles and coworkers demonstrated specific binding of a protein with properties of ferritin H to a conserved CAGTGC motif in the beta globin promoter.135Transient transfection assays revealed that ferritin H repressed synthesis of beta globin, suggesting that ferritin may play a role in hemoglobin switching. 2 IP:IPR000971 IP:IPR000971 activates GO:0009058 Phenotype f11c6498-c8b9-11ee-9133-0050569a1f61 PMC10068482 Because the α or β globin chain gene mutation in the thalassemia trait-induced anemia can cause insufficient Hb synthesis in the red blood cells, this is the major factor resulting in the microcytic erythrocytes in these two OSF patient with thalassemia trait-induced anemia. 2 IP:IPR000971 IP:IPR000971 activates MESH:D013789 Phenotype 0aa9ef5c-3c86-11f0-afc2-0050569a791b 10.1016/j.tcb.2022.02.005 In human thalassemia, exaggerated globin precipitation causes anemia [52]. 2 IP:IPR000971 IP:IPR000971 activates MESH:D013789 Phenotype 51177c6e-cc76-11e5-85cd-001a4ae51247 9288758 Just as protein-truncating mutations in globin produce thalassemia and not sickle cell disease, more profound loss-of-function mutations in pyrin may produce a phenotype much different from FMF. 2 IP:IPR000971 IP:IPR000971 activates GO:0006412 Phenotype 007bc562-c46a-11e5-8491-001a4ae51247 24511086 Moreover, the observed decrease of globin protein levels in differentiated MELHO-1 cells (Figure 2C-D) further supports the conclusion that activated HRI inhibited globin translation. 2 IP:IPR000971 IP:IPR000971 inhibits MESH:D009569 Phenotype a012d150-bc2d-11e5-8d2d-001a4ae51247 10.1016/j.micpath.2006.12.001 The ferrous oxygenated globins are able to oxidize toxic nitric oxide (NO) to yield nitrate[5–7]and resulting ferric form of globin are reduced to the ferrous form by specific reductase and can, therefore, repeat a cycle of NO detoxification[8]. 2 IP:IPR000971 IP:IPR000971 activates MESH:D010100 Phenotype dd43fdb2-bc0d-11e5-8abe-001a4ae51246 PMC3812327 This new gene has a crucial role in mammalian development; fetal globin binds oxygen with a higher affinity, enabling efficient transfer of oxygen from the bloodstream of the mother to the fetus. 2 IP:IPR000971 IP:IPR000971 activates MESH:D001664 Phenotype 82a2080e-45ce-11f0-afc2-0050569a791b 10.1016/j.envres.2021.112523 Red blood cells are destroyed to produce globin and heme, which produce biliverdin (a precursor of bilirubin) and CO under the action of heme oxygenase. 2 IP:IPR000971 IP:IPR000971 inhibits GO:0098754 Phenotype a012d150-bc2d-11e5-8d2d-001a4ae51247 10.1016/j.micpath.2006.12.001 The ferrous oxygenated globins are able to oxidize toxic nitric oxide (NO) to yield nitrate[5–7]and resulting ferric form of globin are reduced to the ferrous form by specific reductase and can, therefore, repeat a cycle of NO detoxification[8]. 2 IP:IPR000971 IP:IPR000971 increases MESH:D007501 Phenotype fd5c3924-ca00-11e5-ab20-001a4ae51246 15863440 With this model in mind, the consequences of haemoglobin S instability became clear to biochemists during the 1980s (Fig. 2).35–3875Impaired stability of the globin leads to accelerated breakdown of the molecule, releasing large quantities of toxic iron and haem compounds into the cell. 2 IP:IPR000971 IP:IPR000971 increases MESH:D007501 Phenotype c39f39c8-335f-11e8-bf76-001a4a160175 25631622 Imbalance of globin chain synthesis in thalassemic erythroid precursor cells leads to denaturation and degradation of excess unbounded α-globin chains, resulting in the release of disintegrated heme and toxic non-transferrin-bound iron species. 2 IP:IPR000971 IP:IPR000971 inhibits MESH:D007501 Phenotype fd5c3924-ca00-11e5-ab20-001a4ae51246 15863440 Haem is contained is a hydrophobic globin pocket that both limits the reaction of iron with oxygen and shields the cell from free radicals produced by the highly reactive iron compounds. 2 IP:IPR000971 IP:IPR000971 activates MESH:D006402 Phenotype 10568bee-bbf9-11e5-9b9d-001a4ae51247 10.1016/j.bcmd.2011.11.004 Introduction Thalassemias are a group of inherited blood diseases caused by defects in the globin genes resulting in either reduction or loss of globin chain synthesis, thereby leading to anemia[1]. 2 IP:IPR000971 IP:IPR000971 activates MESH:D007938 Phenotype 37720c04-0cfc-11f0-b759-0050569a791b 10.1016/S0166-3542(99)00065-0 Initially, we demonstrated that AZT (Weidner and Sommadossi, 1990), as well as its metabolite 3′-amino-3′-deoxythymidine (Weidner et al., 1992), decreased steady state levels of globin mRNA in butyric acid-induced differentiating human K-562 leukemia cells. 2 IP:IPR000971 IP:IPR000971 activates MESH:D007938 Phenotype a27845fa-cbf1-11e5-a19a-001a4ae51247 10395935 Moreover, Sommadossi and co-workers have reported that AZT and its catabolite 3′-amino-3′-deoxythymidine inhibit both hemoglobin synthesis and globin gene transcription in butyric acid-induced K562 leukemia cells[13,14]and in human hepatocytes[15]. 2 IP:IPR000971 IP:IPR000971 inhibits MESH:D008070 Phenotype 5514f792-bc31-11e5-8d2d-001a4ae51247 10.1016/j.abb.2005.02.006 Hemin-free globin rather than intact metHb specifically suppresses lipopolysaccharide activation of macrophages and thereby confers protection in peritonitis and endotoxemia. 2 IP:IPR000971 IP:IPR000971 inhibits GO:0030154 Phenotype c4440492-c9ff-11e5-b88f-001a4ae51247 15037632 Reverse transcription-semiquantitative PCR analysis of E-ALAS and β-major globin genes, two GATA-1 target genes induced upon erythroid differentiation, revealed reduced expression of these transcripts in cells exogenously expressing TACC3 upon Me2SO-induced differentiation (Fig. 6c). 2 IP:IPR000971 IP:IPR000971 activates MESH:D051379 Phenotype 267478b6-cb8d-11e5-9498-001a4ae51246 10995745 Studies of human globin chain synthesis in NF2d9 nullizygous mice will address this question. 2 IP:IPR000971 IP:IPR000971 activates MESH:D003643 Phenotype b3c0fef6-335f-11e8-9fbf-001a4a160176 25633854 Accumulation and deposition of the unmatched globin chains in erythroid precursors cause the premature death of these cells in the bone marrow[2]. 2 IP:IPR000971 IP:IPR000971 activates MESH:D001710 Phenotype bc1d2918-bc3c-11e5-8abe-001a4ae51246 10.1016/S1359-6446(05)03644-5 The inhibition of globin cDNA synthesis dramatically reduces the relative amount of anti-sense, biotin-labeled cRNA corresponding to the hemoglobin transcripts. 2 IP:IPR000971 IP:IPR000971 activates MESH:D006427 Phenotype 7ca07356-d381-11e5-85cd-001a4ae51247 PMC349646 The levels if i antigen, embryonic globin chains, and embryonic globin mRNA increased substantially after exposure of the cells to hemin in suspension culture. 2 IP:IPR000971 IP:IPR000971 activates MESH:D001663 Phenotype 82a2080e-45ce-11f0-afc2-0050569a791b 10.1016/j.envres.2021.112523 Red blood cells are destroyed to produce globin and heme, which produce biliverdin (a precursor of bilirubin) and CO under the action of heme oxygenase. 2 IP:IPR000971 IP:IPR000971 inhibits GO:0070527 Phenotype 0d2d18ae-bbd9-11e5-8abe-001a4ae51246 10.1016/j.nutres.2008.03.017 It has been shown that platelet aggregation was inhibited by rat globin or a globin-related protein[38]; by a defined region (glycine-486–lysine-502) of high molecular weight kininogen[39]; by a synthetic, 18-amino acid residue peptide derived from a hydrophilic domain of a cloned platelet type I collagen receptor[40]; by sheep lactoferrin[41]; by largerκ-casein oligopeptides[42,43]; and by kallikrein[44]. 2 IP:IPR000971 IP:IPR000971 activates MESH:D000740 Phenotype 0aa9ef5c-3c86-11f0-afc2-0050569a791b 10.1016/j.tcb.2022.02.005 In human thalassemia, exaggerated globin precipitation causes anemia [52]. 2 IP:IPR000971 IP:IPR000971 activates MESH:D000740 Phenotype ecb4372a-cd2f-11e5-b6ad-001a4ae51246 7499303 The resulting globin chain imbalance due to unimpeded α-globin expression leads to precipitation of globin polypeptide chains in developing erythroid cells, and the ensuing anemia. 2 IP:IPR000971 IP:IPR000971 activates MESH:D000740 Phenotype bab7bf98-b7d1-11e6-a2fa-001a4ae51246 27890361 Thalassemia syndromes are a heterogeneous group of anemias which are caused by genetic defects in globin genes. 2 IP:IPR000971 IP:IPR000971 activates GO:0030218 Phenotype 0afa5c14-2cbc-11f0-b759-0050569a791b 10.1182/blood.V98.13.3618 In any case, hGM-CSF has the effect on the globin synthesis in erythropoiesis of hGMR-expressing mouse embryos. 2 IP:IPR000971 IP:IPR000971 activates GO:0030218 Phenotype 7807f8c8-c46d-11e5-91a7-001a4ae51247 PMC4321326 In mouse models of thalassemia, bone marrow erythroferrone expression is increased.35These discoveries propose a model that globin chain imbalance causes ineffective erythropoiesis, resulting in anemia and increased Epo production, which produces expanded erythropoiesis and enhanced erythroferrone production, which acts on the liver to suppress hepcidin. 2 IP:IPR000971 IP:IPR000971 inhibits GO:0030218 Phenotype f5d36432-867c-11f0-86f5-0050569a1f61 PMC7922838 Imbalances of globin chains cause haemolysis and impair erythropoiesis [1,2]. 2 IP:IPR000971 IP:IPR000971 inhibits GO:0030218 Phenotype 333aea78-c8de-11e5-9cb8-001a4ae51247 PMC1852217 The hallmarks of HRI deficiency in these 3 anemias are increased globin inclusions, decreased red blood cell number with normal MCV and MCH, and aggravation of ineffective erythropoiesis. 2 IP:IPR000971 IP:IPR000971 activates GO:0015671 Phenotype 40bc98ac-bbde-11e5-8abe-001a4ae51246 10.1016/j.aquatox.2010.09.011 Ultimately, the globin molecules are recognized to support oxygen transport in a variety of organs including blood, muscle and the CNS and decreased transcript expression in response to RDX exposure indicates potential decreased capacity for systemic oxygen transport. 2 IP:IPR000971 IP:IPR000971 activates MESH:D012805 Phenotype 1afdaaae-bbe6-11e5-8abe-001a4ae51246 PMC3263337 Because sickle cell trait is caused by a mutation in beta globin, and α thalassaemia by a mutation in alpha globin, this is a clear example of epistasis (here defined as the presence of a particular allele at one locus affecting the phenotypic outcome of an allele at a second locus). 2 IP:IPR000971 IP:IPR000971 activates PF:PF09010 ProteinFamily 26d977f4-44b0-11e8-ab82-001a4a160175 PMC5892615 Introduction intro Thalassemia is the most common inherited blood disorder in Southeast Asia, which is caused by reduced or absent synthesis of the globin chains of hemoglobin leading to imbalance of the globin chains. 2 IP:IPR000971 IP:IPR000971 activates FPLX:PKA ProteinFamily 5b5824d6-bc3a-11e5-8d2d-001a4ae51247 PMC3412720 Activation of globin production by transcription factor NFE2 is stimulated by cAMP-dependent protein kinase (PKA) in erythroid cells [10]. 2 IP:IPR000971 IP:IPR000971 inhibits IP:IPR006361 ProteinFamily 6c0656e2-3747-11e8-8636-001a4a160175 26593548 It is known that heme Fe is poorly absorbed when consumed as a prosthetic group (Conrad et al., 1966), but its absorption increases when ingested as Hb (heme bound to four globin chains) (Conrad et al., 1966; Layrisse & Martínez-Torres, 1972), presumably because heme Fe absorption is facilitated by degraded protein substances from Hb: globin protein prevents the polymerization of heme (Conrad et al., 1966). 2 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily 306a334e-bc40-11e5-9b9d-001a4ae51247 10.1016/j.freeradbiomed.2005.04.003 This process might reflect a “hole” tunneling process manifesting a long-range electron tunneling in the opposite direction, which resembles electron transfer throughout the globin that entails peroxide-induced oxidation of the heme protein[9,17]. 2 IP:IPR000971 IP:IPR000971 decreases IP:IPR006361 ProteinFamily d4d9b932-bbd6-11e5-8abe-001a4ae51246 10.1016/j.cell.2004.08.014 Thus, it appears that increasing intracellular heme levels during early erythropoiesis triggers the onset of globin protein synthesis, which ultimately reduces the levels of uncommitted heme. 2 IP:IPR000971 IP:IPR000971 increases IP:IPR006361 ProteinFamily c39f39c8-335f-11e8-bf76-001a4a160175 25631622 Imbalance of globin chain synthesis in thalassemic erythroid precursor cells leads to denaturation and degradation of excess unbounded α-globin chains, resulting in the release of disintegrated heme and toxic non-transferrin-bound iron species. 2 IP:IPR000971 IP:IPR000971 inhibits IP:IPR006361 ProteinFamily c5907196-bc4e-11e5-8abe-001a4ae51246 10.1016/S0969-2126(03)00166-7 Our results reveal that a substantially conserved globin fold can support reversible heme hexacoordination through structural flexibility in the NGB region comprised between C and E helices. 2 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily 6c0656e2-3747-11e8-8636-001a4a160175 26593548 Data obtained in Caco-2 cell models supports the theory that globin promotes apical uptake of heme (Follett, Suzuki, & Lonnerdal, 2002) and the possible existence of a protein located in the apical region of enterocytes that negatively regulates the absorption of heme and/or polypeptides that may help in the absorption of heme Fe (Uc, Stokes, & Britigan, 2004). 2 IP:IPR000971 IP:IPR000971 increases IP:IPR006361 ProteinFamily 1210e66c-351b-11e8-a51f-001a4a160176 28254242 This was demonstrated by a report showing that inhibition of translation in erythroid cells led to heme accumulation in mitochondria, and that globin significantly enhanced heme release from such heme-laden mitochondria[26]. 2 IP:IPR000971 IP:IPR000971 decreases IP:IPR000971 ProteinFamily 2f19023e-377e-11e8-87fd-001a4a160176 10582345 Thus it is possible that the excess of foetal globin results from the inability of the residual BKLF to repress foetal globin transcription. 2 IP:IPR000971 IP:IPR000971 activates IP:IPR000971 ProteinFamily 57fc359c-cc76-11e5-b6ad-001a4ae51246 9242673 The level of globin gene expression in E progenitor cells during lineage commitment is modulated directly by cell-specific transcription factors that bind to specific motifs in the locus control region and proximal globin gene promoters. 2 IP:IPR000971 IP:IPR000971 activates IP:IPR000971 ProteinFamily 007bc562-c46a-11e5-8491-001a4ae51247 24511086 Moreover, the observed decrease of globin protein levels in differentiated MELHO-1 cells (Figure 2C-D) further supports the conclusion that activated HRI inhibited globin translation. 2 IP:IPR000971 IP:IPR000971 activates IP:IPR000971 ProteinFamily 757cf550-bc3d-11e5-8d2d-001a4ae51247 PMC1907364 KLF13 was cloned as a candidatetrans-activator of γ globin expression.14KLF13 activates γ globin promoter activity under transient transfection assays.14,15However, no change in endogenous γ globin gene expression was observed when KLF13 was silenced in K562 cells using RNAi. 2 IP:IPR000971 IP:IPR000971 activates FPLX:EIF4A ProteinFamily 30261e2c-cb2a-11e5-a6cd-001a4ae51247 12183465 For example, mammalian eIF4A, which is required for translation initiation of all mRNA, is stimulated more efficiently by poly(U) than by globin mRNA (20). 2 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 4d434aea-bbf6-11e5-8abe-001a4ae51246 10.1016/j.cbpb.2006.11.031 Hemoglobin expression profile induced by hypoxia Specific waves of transcription of β-like globin gene of chick genome, appearing during the interval between 5 and 12 days of incubation, had been determined by transcriptionin vitroand southern blots analysis (Landes et al., 1982). 2 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 3c9c874e-bc53-11e5-8d2d-001a4ae51247 PMC3621302 Introduction Sickle cell disease (SCD) is a group of disorders caused by a mutation in the sequence of beta globin, leading to polymerized hemoglobin (sickle hemoglobin, hemoglobin S), hemolytic anemia, painful vaso-occlusive events, vascular remodeling, acute and chronic organ injury, and shortened lifespan. 2 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily e4fca5ce-1bbf-11f0-a2ca-0050569a1f61 10.1016/j.jmb.2023.168343 At the β-globin locus, theHBBP1pseudogene contributes to the developmental control of γ-globin transcription, and theHBBP1genomic region is required for γ-globin silencing in adult erythroblasts.19During early development, α-like (ς) and β-like (ε) globin genes are expressed to produce the embryonic hemoglobin heterotetramer (ς2ε2). 2 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 7b8ca942-3754-11e8-a51f-001a4a160176 25679069 Between 6 and 8 wk of gestation there is a switch leading to expression of the alpha and the gamma globin genes, that produces the fetal hemoglobin – HbF (alpha-2, gamma-2). 2 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 68499fb0-bc50-11e5-8abe-001a4ae51246 PMC4928484 A point mutation in the β globin gene causes hemoglobin to polymerize in hypoxic and acidic conditions and erythrocytes to sickle. 2 IP:IPR000971 IP:IPR000971 activates PF:PF12338 ProteinFamily 2779563a-390b-11e8-a34b-001a4a160175 25450870 In combination with hematologic data, the immunochromatographic strip test could rule out mass populations for further α0-thalassemia detection by polymerase chain reaction–based analysis, and has the potential to replace testing for Hb H inclusion bodies as it appears to be more sensitive, more specific, and less labor intensive.Thalassemia is an autosomal recessive inherited genetic disorder of the red blood cells (RBCs) caused by the reduction or absence of one or more globin chains of hemoglobin (Hb) molecules. 2 IP:IPR000971 IP:IPR000971 activates GO:0042592 Phenotype 1ec7e32a-c73b-11ee-b22c-0050569a1f61 10.1016/j.jhazmat.2023.132124 We therefore proposed the hypothesis: Some specific globin protein mediating heme homeostasis signaling can be involved in controlling PS-NPs-induced transgenerational toxicity.|||Additionally, heme homeostasis induced by globin proteins controlled the response to hypoxia stress in ectothermic vertebrates[31]. 2 IP:IPR000971 IP:IPR000971 inhibits MESH:D000755 Phenotype f31ee52c-5caf-11e7-af4d-001a4ae51247 PMC4667977 A significant body of biochemical, epidemiologic, clinical, and pharmacologic data has demonstrated that adequately elevated fetal globin protein levels are associated with less severe anemia in β-thalassemia patients and reduced clinical complications in sickle cell disease[2–6,19,59,63,64].|||Discussion A significant body of biochemical, epidemiologic, clinical, and pharmacologic data has demonstrated that adequately elevated fetal globin protein levels are associated with less severe anemia in β-thalassemia patients and reduced clinical complications in sickle cell disease[2–6,19,59,63,64]. 2 IP:IPR000971 IP:IPR000971 activates MESH:D000745 Phenotype fc83e5c4-3385-11e8-8f56-001a4a160175 26852663 Introduction β-Thalassemia major (BTM) is a hereditary hemolytic anemia caused by defect in β globin chain synthesis.|||β-Thalassemia major (BTM) is a hereditary hemolytic anemia caused by defect in β globin chain synthesis. 2 IP:IPR000971 IP:IPR000971 activates MESH:D000745 Phenotype 41848d1c-3409-11e8-a51f-001a4a160176 25816754 Introduction In Egypt, β-thalassemia is the most common hereditary hemolytic anemia caused by mutation of β globin gene (El-Tagui et al., 2013).|||In Egypt, β-thalassemia is the most common hereditary hemolytic anemia caused by mutation of β globin gene (El-Tagui et al., 2013). 2 IP:IPR000971 IP:IPR000971 activates MESH:D003643 Phenotype 292e4b58-c468-11e5-91a7-001a4ae51247 PMC3648058 "Thus, our initial hypothesis that decreased globin chain production leads to excess free heme toxicity and early erythroid progenitor cell death is incorrect and is unlikely the cause for erythroid precursor death in DBA.|||In this study, we directly test the hypothesis that decreased globin chain production leads to increased free heme and early erythroid progenitor cell death by developing erythroid model systems that are devoid of all adult globin chains." 2 IP:IPR000971 IP:IPR000971 activates MESH:D006453 Phenotype 2c6f8908-c8e6-11e5-9ad8-001a4ae51247 18024611 "The globin mutations that lead to hemoglobinopathies such as sickle cell disease or thalassemia have a profound effect on the RBC membrane.|||In summary, the mutations in the globin genes that underlie hemoglobinopathies have profound effects on RBC membranes." 2 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily a72985f6-ab4c-11e6-9ac8-001a4ae51246 PMC5010382 Because more than 95% of the protein content of red blood cells is hemoglobin, any mutation or event that ubiquitously impedes protein transcription or translation could delay globin up-regulation and result in excessive heme.|||In patients with DBA, globin synthesis initiates slowly Figure 2also shows heme and globin measurements. 2 UNIPROT:Q99558 decreases IP:IPR000971 IP:IPR000971 Protein d917e8a2-bbd6-11e5-956b-001a4ae51247 10.1016/j.cell.2006.11.044 We have previously shown that removal of the mouse sequence (HS -26), which is the equivalent of the human major regulatory element (HS -40), from the endogenous locus only reduces mouse α globin expression to ∼50% of normal, and homozygotes for this allele survive with only mild anemia rather than developing hydrops fetalis (Anguita et al., 2002). 2 UNIPROT:P12643 decreases IP:IPR000971 IP:IPR000971 Protein 12ef69c4-c8de-11e5-a1fd-001a4ae51246 16908518 Indeed, Smad10 inhibited induction of globin expression by BMP2 at similar doses to those required for neural induction (Fig. 1B). 2 UNIPROT:P02144 activates IP:IPR000971 IP:IPR000971 Protein 574009c0-334a-11e8-b868-001a4a160176 22060797 The heating of myoglobin, oxymyoglobin and metmyoglobin pigments in normal (pH 5.3–5.7) fresh muscle produces globin ferrihemochrome, the grey pigment of cooked meat (Mendenhall, 1989). 2 CHEBI:48947 increases IP:IPR000971 IP:IPR000971 Chemical 96714580-5c97-11e7-8c5f-001a4ae51246 PMC5235323 CVA increases gamma globin mRNA levels and fetal HB in JK-1 and TMbmEPSCs We then examined the effects of CVA on γ-globin gene expression in K562, JK-1 and TMbmEPSCs using either semi-quantitative PCR or real time PCR or both. 2 UNIPROT:Q13351 activates IP:IPR000971 IP:IPR000971 Protein 9d3affbc-c8de-11e5-9624-001a4ae51246 16606611 The results described in this paper are fully consistent with the competition model for globin gene switching (7) and suggest that developmental stage-specific changes in EKLF abundance mediate the competitive interactions of globin gene family members with the powerful locus control region. 2 UNIPROT:Q13351 increases IP:IPR000971 IP:IPR000971 Protein 3b2e6234-ca5d-11e5-9088-001a4ae51247 12920040 Note added at proofs:Experiments performed since this manuscript was submitted, in which the CBP expression construct was driven by a more powerful promoter (CMV-CBP, kindness of Dr. Jenny Ting), show a modest up-regulation of EKLF-driven expression of the embryonic murine globin gene promoter by CBP, as previously reported at the adult β-globin gene.26As with p300 in the current manuscript, SCFAs further augment CBP with EKLF-driven expression from a murine embryonic globin gene promoter, at up to 2- to 5-fold. 2 UNIPROT:Q13351 activates IP:IPR000971 IP:IPR000971 Protein 091408be-352a-11e8-9192-001a4a160175 25528728 The deficiency of KLF1 in mouse results in defective erythropoiesis in fetal liver and reduced the transcription of the β major globin gene[4,5]. 2 FPLX:Proteasome activates IP:IPR000971 IP:IPR000971 ProteinFamily 24646422-c9fe-11e5-be63-001a4ae51246 15297454 Effects of Proteasome and Deubiquitylation Inhibitors on Ubiquitin-mediated Proteolytic Degradation of Nascent Globin Chains in the Presence of High (5 mm) and Low (1.5 mm) ATP Levels—We attempted to clarify whether the absence of radiolabeled globin chain bands after the addition of ubiquitin and ERS prior to initiation of translation is dependent on ubiquitylation of nascent globin chains and subsequent proteolytic degradation through the 26 S proteasome. 2 FPLX:Ubiquitin inhibits IP:IPR000971 IP:IPR000971 ProteinFamily 24646422-c9fe-11e5-be63-001a4ae51246 15297454 Ubiquitin-mediated Proteolytic Degradation of Nascent Globin Chains Made in a Cell-free System—Newly translated nascent globin chains must undergo folding, heme insertion, and assembly with partner globin chains to form functional heterodimers and tetramers of Hb (9). 2 FPLX:STAT5 increases IP:IPR000971 IP:IPR000971 ProteinFamily 1d599dfe-d9fa-11ee-9133-0050569a1f61 10.1182/blood.V92.4.1104 Also, in the case of exogenously expressed STAT5A mutants, this is presumed in each study to include dominant-negative inhibition of any contributions by STAT5B based on the ability of A and B isoforms to heterodimerize.25Therefore, these observations consistently suggest that STAT5 normally may mediate Epo effects on globin gene expression and possibly to additional events involved in the terminal differentiation of red blood cells. 2 UNIPROT:P29466 activates IP:IPR000971 IP:IPR000971 Protein 836c7604-bc3d-11e5-8d2d-001a4ae51247 10.1016/j.jmb.2007.11.074 72 The blood phenotype observed in these mice as well as in transgenic animals is in agreement with several earlier reports that investigated the functions of small Maf proteins by gain of function and loss of function studies in cell culture models.76Conditional over-expression of MafK was shown to induce erythroid cell differentiation, leading to the accumulation of hemoglobin and globin gene transcripts in non-treated as well as in DMSO-induced murine erythroid leukemia (MEL) cells.77,78On the other hand, a dominant-negative mutant of MafK reduced NF-E2 DNA binding activity and impaired globin gene expression in MEL cells.79The forced expression of p45 or tethered p45/MafK and p45/MafG heterodimers rescued globin gene synthesis in CB3 erythroleukemia cells that do not express p45.31,79,80It is of interest to note that small Mafs appear to occupy the regulatory region of the globin gene, the locus control region (LCR), before the induction of erythroid differentiation.81Together, these results suggested that small Mafs have an important role in the differentiation program of erythroid cells. 2 MESH:D015215 decreases IP:IPR000971 IP:IPR000971 Phenotype 3afcdebc-377f-11e8-87fd-001a4a160176 10958868 Moreover, AZT and its catabolite 3′-amino-3′-deoxythymidine were also reported to inhibit hemoglobin synthesis and globin gene transcription in either differentiated K562 cells[6,7]and human hepatocytes[8]. 2 UNIPROT:P03973 activates IP:IPR000971 IP:IPR000971 Protein 208a2952-bc2c-11e5-8abe-001a4ae51246 10.1016/j.fsi.2013.02.028 The effect of MOS on serum ALP, globin and lysozyme in Allogynogenetic crucian carp The serum ALP activity significantly increased significantly 1d after infection in the group of 240, 480 mg/kg MOS, 2d after infection in the group of 120, 240, 480 mg/kg MOS compared to pre-infection levels (P< 0.05) (Fig. 3A). 2 MESH:D000077337 increases IP:IPR000971 IP:IPR000971 Phenotype 3ac895a8-ca5d-11e5-a3f7-001a4ae51246 PMC2808412 We have previously shown that hydroxamic acid derivatives of butyrate and propionate are strong γ gene inducers and exert their effects in concentrations that are almost 1 order of magnitude lower than those of the parent compounds.7Two other hydroxamic acid derivatives, SAHA and SBHA, induce γ globin gene expression in concentrations that are approximately 2 orders of magnitude lower than those of butyrate and propionate.7Here, we report induction of γ gene expression by 3 classes of HDAC inhibitors: analogues of trichostatin A, analogues of trapoxin, and scriptaid and its analogues. 2 UNIPROT:P46100 increases IP:IPR000971 IP:IPR000971 Protein 648cfbf4-ca5d-11e5-9bd2-001a4ae51247 14592816 At present it is not yet clear how ATRX contributes to normal α globin gene expression, or at what stage(s) of development and red cell differentiation ATRX is involved. 2 UNIPROT:Q9NXR7 activates IP:IPR000971 IP:IPR000971 Protein 37a72a28-3555-11e8-9192-001a4a160175 10720693 Whether the γBRE is specific for the γ promoter or can stimulate other globin promoters, i.e., β gobin, will be tested experimentally. 2 CHEBI:30762 activates IP:IPR000971 IP:IPR000971 Chemical 33c064d6-c46b-11e5-85e4-001a4ae51246 PMC4208286 These results confirm that Sal enhances globin translation efficiency at 24 hours, as evidenced by a greater number of actively translating ribosomes occupying the transcripts. 2 CHEBI:30762 increases IP:IPR000971 IP:IPR000971 Chemical 33c064d6-c46b-11e5-85e4-001a4ae51246 PMC4208286 The most dramatic posttranscriptional HbF induction was elicited by salubrinal (Sal), a pharmacologic enhancer of p-eIF2α, which increased HbF up to 4.5-fold without altering globin mRNA levels, cellular differentiation, or total Hb content. 2 CHEBI:46024 inhibits IP:IPR000971 IP:IPR000971 Chemical 2091f036-bc10-11e5-9b9d-001a4ae51247 10.1016/S0959-437X(02)00291-5 Additionally, treatment of fetal liver cells with butyrate or trichostatin A (TSA) led to an increase in acetylation at the silenced embryonic globin gene promoter, but did not reactivate its transcription. 2 FPLX:HDAC decreases IP:IPR000971 IP:IPR000971 ProteinFamily 0831b182-bbf9-11e5-9b9d-001a4ae51247 10.1016/S1079-9796(03)00024-X The goal of the studies reported here was to test directly whether inhibition of histone deacetylase activates γ globin gene expression. 2 FPLX:HDAC decreases IP:IPR000971 IP:IPR000971 ProteinFamily 3b2e6234-ca5d-11e5-9088-001a4ae51247 12920040 SCFAs, such as butyrate and propionate, have been shown to have an HDAC function in vitro.66-68EKLF, SP1, and SP3 have been reported to recruit HDACs,64,69,70and HDAC inhibitors can further transactivate EKLF and H/FATs at the adult β-globin gene promoter.28The induction of fetal/embryonic globin gene expression by HDAC inhibitors40suggests an etiologic role for the release of HDAC-mediated repression in the net up-regulation of embryonic globin genes. 2 CHEBI:35223 inhibits IP:IPR000971 IP:IPR000971 Chemical 7e3f55e6-3406-11e8-8636-001a4a160175 PMC5633526 By virtue of its vacuolar localization and its catalytic activity at the acidic pH of the vacuole[5], PfA-M1 is positioned to be a key catalyst for degrading these short globin peptides to individual amino acids. 2 CHEBI:73509 activates IP:IPR000971 IP:IPR000971 Chemical 0368f4ce-0e67-11f0-b759-0050569a791b 10.1182/blood.V91.3.798 The significance of heme deficiency in β-major globin synthesis is also corroborated by the fact that globin protein synthesis was partially restored by treatment of ALAS-E(-) ES cells with exogenous ALA. 2 UNIPROT:Q9Y5W3 activates IP:IPR000971 IP:IPR000971 Protein d99a0cd0-ca02-11e5-b88f-001a4ae51247 PMC1895257 Our results show that KLF2 positively regulates the human (ϵ) and murine (Ey and βh1) embryonic globin genes at both E10.5 and E12.5, in the yolk sac, which is the site of primitive erythropoiesis. 2 FPLX:NFE activates IP:IPR000971 IP:IPR000971 ProteinFamily 4d263fcc-47f1-11e6-9af9-001a4ae51247 10.1074/jbc.273.22.13593 We have recently demonstrated a protein/protein interaction between NF-E2 and hTAFII130, which allows juxtaposition of the LCR and proximal globin promoters (51). 2 FPLX:NFE activates IP:IPR000971 IP:IPR000971 ProteinFamily 143092fa-bc3f-11e5-8abe-001a4ae51246 10.1016/S0968-0004(03)00089-6 Several studies have suggested a direct role for erythroid-specific enhancer-binding protein nuclear factor-erythroid 2 (NF-E2) in LCR-dependent activation of globin genes[13,14]. 2 FPLX:NFE activates IP:IPR000971 IP:IPR000971 ProteinFamily 57fc359c-cc76-11e5-b6ad-001a4ae51246 9242673 NF-E2 binds to the NF-E2/Ap-1 tandem repeat and activates globin gene activity. 2 CHEBI:30751 increases IP:IPR000971 IP:IPR000971 Chemical 3b2e6234-ca5d-11e5-9088-001a4ae51247 12920040 We are working to clarify the role played by these factors in vivo; nonetheless, transcription factor acetylation by SCFAs is novel and may be one of the ways in which SCFAs, as a class of compounds, act to up-regulate embryonic globin gene expression during adult erythroid differentiation. 2 CHEBI:30751 increases IP:IPR000971 IP:IPR000971 Chemical 47f3f2fa-c8e0-11e5-a1fd-001a4ae51246 PMC1895523 Although generalized acetylation of histones to confer chromatin accessibility was initially considered a mechanism of γ-globin gene activation by the butyrates, other SCFAs induce fetal globin expression without causing generalized histone acetylation.24-26Thus, specific molecular events underlying γ-globin gene induction in response to SCFAs have not been entirely elucidated, and a better understanding would be useful for the development of high-potency therapies. 2 CHEBI:30751 activates IP:IPR000971 IP:IPR000971 Chemical 3b2e6234-ca5d-11e5-9088-001a4ae51247 12920040 This cell line allows the study of the molecular mechanisms underlying SCFA-mediated inducibility of fetal/embryonic globin genes in an adult erythroid milieu. 2 CHEBI:30751 increases IP:IPR000971 IP:IPR000971 Chemical 2c444574-bc1e-11e5-8abe-001a4ae51246 PMC2254528 Short-chain fatty acids, such as butyric acid, stimulate fetal globin gene expression in experimental models, including patients’ cultured cells, transgenic mice, and baboons[8–16]. 2 FPLX:HIF1 decreases IP:IPR000971 IP:IPR000971 ProteinFamily 1afb7b2a-cbf0-11e5-83a8-001a4ae51246 9973316 "On the other hand, one might postulate that HIF-1 binds directly to a putative HIF-1 binding site present in the locus control region or promoters of the β-globin cluster, thereby repressing embryonic globin expression and/or activating fetal/adult globin expression." 2 FPLX:HIF1 increases IP:IPR000971 IP:IPR000971 ProteinFamily a3e37014-bbd8-11e5-8abe-001a4ae51246 PMC2228317 This could indicate that HIF-1 mediates induction of these genes upon anoxia treatment and that HIF-1 activity is modulated by insulin/IGF-1 signaling, or that HIF-1 and DAF-2 each act to regulate the expression of these globin genes. 2 MESH:D006918 increases IP:IPR000971 IP:IPR000971 Phenotype 44f4b242-c471-11e5-a92e-001a4ae51246 PMC2710936 SCFA-mediated up-regulation of globin gene expression in vitro was detectable in most cells and, in the absence of ins/EPO, affected primarily βH1in the murine andGγ in the human loci.Gγ, but notAγ, is up-regulated by hydroxyurea or butyrate in K562 cells.22,43Sangeman et al22described a cAMP-response element (CRE) at an ATF/CREB binding site in theGγ promoter, absent from theAγ promoter, through which butyrate acts in K562s. 2 MESH:D006918 increases IP:IPR000971 IP:IPR000971 Phenotype f0ca60bc-d9b2-11ee-9133-0050569a1f61 10.1016/S0301-472X(98)00010-1 In particular, hydroxyurea and butyrate both have been shown to raise fetal globin levels in cultured erythroid progenitors[7–9]. 2 MESH:D006918 activates IP:IPR000971 IP:IPR000971 Phenotype dd13940c-340a-11e8-9fbf-001a4a160176 27931853 Dr. Papayannapoulou's ground-breaking discoveries on globin switching and the induction of fetal γ-globin in adult cells led to the clinical use of fetal globin stimulators such as hydroxyurea for the treatment of sickle cell anemia[1–3]. 2 UNIPROT:P04040 inhibits IP:IPR000971 IP:IPR000971 Protein 1db7be4c-bc40-11e5-8abe-001a4ae51246 10.1016/j.freeradbiomed.2005.11.017 2Aazide inhibition of catalase significantly enhanced membrane globin deposition following 20 h incubation at 37°C. Associated with the ongoing oxidative stress within the cell, significant degradation of specific membrane proteins is noted (Fig. 2B). 2 MESH:D003907 increases IP:IPR000971 IP:IPR000971 Phenotype 8a51b7c4-bbff-11e5-9b9d-001a4ae51247 10.1016/j.bbrc.2006.05.130 We observed that the simultaneous addition of dexamethasone and SCF (Kit-L) triggered a marked fetal globin gene expression when compared with the erythroid cultures grown in other two dexamethasone free differentiation media. 2 UNIPROT:P35658 increases IP:IPR000971 IP:IPR000971 Protein 67b62c8e-ca02-11e5-ab20-001a4ae51246 PMC1432098 TwoXenopussteel homologues,Xsl-1andXsl-2, were recently reported and both are expressed in the prospective ectoderm.21Moreover, low doses of soluble murine steel protein can induce globin expression when added to the culture media ofXenopusventral mesoderm explants.22The consequences of disrupting steel function inXenopushave not been reported, but in mouse loss of steel or its receptor causes severe macrocytic anemia due to defects in proliferation of definitive erythroid progenitors.23Little is known, however, about steel function during primitive murine hematopoiesis. 2 MESH:D000242 increases IP:IPR000971 IP:IPR000971 Phenotype 8b6ed240-bbff-11e5-8abe-001a4ae51246 10.1016/j.bbrc.2006.03.203 Some studies had shown regulatory roles of the cAMP pathway in erythropoiesis[14,44,45], but it remains unclear whether the cAMP pathway contributes to the expression of human β-like globin genes during development. 2 MESH:D013792 increases IP:IPR000971 IP:IPR000971 Phenotype aba6461a-c8e8-11e5-a1fd-001a4ae51246 PMC2018668 As demonstrated here, thalidomide induces γglobin expression through a mechanism that involves ROS-dependent activation of p38 MAPK cell signaling and histone H4 acetylation. 2 UNIPROT:P39019 activates IP:IPR000971 IP:IPR000971 Protein a5bea764-4558-11f0-b8fe-0050569a1f61 PMC9185154 A unifying pathophysiologic concept was introduced by our group several years ago.3We hypothesized that the anemia in DBA, as well as in del(5q) myelodysplastic syndrome (MDS) phenocopying DBA with an acquired loss of RPS14, is due to slowed globin chain synthesis and secondary heme toxicity. 2 UNIPROT:Q05066 increases IP:IPR000971 IP:IPR000971 Protein 850590f1-f574-11eb-8e03-001a4a160176 32653411 We observed significantly increased γ- globin gene transcription and HbF expression mediated by TDF in K562 cells. 2 UNIPROT:Q14839 inhibits IP:IPR000971 IP:IPR000971 Protein 5c6e759c-3c95-11f0-8cae-0050569a1f61 PMC9302451 Brg1 is required for β-globin regulation and erythropoiesisin vivo, while CHD4 mediates silencing of fetal globin gene in adult erythroid cells (Amaya et al., 2013;Bultman et al., 2005). 2 UNIPROT:P56192 activates IP:IPR000971 IP:IPR000971 Protein ecc8da18-cd2f-11e5-888a-001a4ae51246 7499351 MARs might mediate an attachment between individual β globin family genes and the β globin LCR (which also contains MARs)(19), possibly having some role in globin switching. 2 UNIPROT:Q9H165 inhibits IP:IPR000971 IP:IPR000971 Protein e65c1ad0-3c5d-11f0-afc2-0050569a791b PMC9372373 Targeting BCL11A to reverse the physiological fetal-to-adult globin switch to increase HbF and concurrently reduce HbS has clear advantages. 2 UNIPROT:Q9H165 decreases IP:IPR000971 IP:IPR000971 Protein dd3ad1a2-3405-11e8-b868-001a4a160176 PMC5911283 These methods for gene editing have entered the clinic, with the first study using ZFNs to disrupt the HIVCCR5coreceptor in peripheral blood T cells from patients infected by HIV, rendering the cells relatively resistant to HIV infection.45Other studies nearing clinical trials will seek to disrupt theCCR5gene in HSCs of HIV-infected patients or disrupt the gene encoding a protein(Bcl11a)that represses expression of fetal globin to turn on the fetal hemoglobin as a way to treat β-thalassemia and sickle cell disease. 2 MESH:D003868 inhibits IP:IPR000971 IP:IPR000971 Phenotype 1c7efe58-bc4c-11e5-ac4e-001a4ae51246 10.1016/j.exppara.2006.05.002 Electrophoretic analysis showed that dequalinium inhibits globin proteolysis (intact band at 14.4 kDa,Fig. 3). 2 UNIPROT:P01033 inhibits IP:IPR000971 IP:IPR000971 Protein e25235a2-bbff-11e5-9b9d-001a4ae51247 PMC1973161 The A-region of IL-2Rβ is essential for IL-2-mediated inhibition of Epo-induced globin gene expression IL-2 and IL-3 induce activation of similar, but not identical, signaling events[2]. 2 UNIPROT:P01033 activates IP:IPR000971 IP:IPR000971 Protein df2c38fe-935e-11e7-82ff-001a4ae51246 12498775 Various hypotheses may account for the differences observed in terms of HbF reactivation between primates under acute stress conditions who increase HbF in response to rHuEpo, primates in chronic erythroid expansion who do not, and mice that increase β-min globin synthesis under both acute and chronic stimulation by an endogenous source of Epo. 2 UNIPROT:P08700 decreases IP:IPR000971 IP:IPR000971 Protein e25235a2-bbff-11e5-9b9d-001a4ae51247 PMC1973161 LG-Stat5-induced globin gene expression is inhibited by IL-3, which activates Stat5 but does not induce globin gene expression. 2 UNIPROT:P04280 increases IP:IPR000971 IP:IPR000971 Protein 46c417ce-c46d-11e5-9cc6-001a4ae51246 PMC4182146 Very rarely, in myeloid neoplasms, such as myelodysplastic syndromes[11]and occasionally PMF[12,13], the neoplastic clone can modulate globin gene transcription, inducing similar conditions. 2 CHEBI:64103 increases IP:IPR000971 IP:IPR000971 Chemical 37a72a28-3555-11e8-9192-001a4a160175 10720693 Sodium butyrate (NaB) also induces globin gene expression and Hb F production in colonies derived from neonatal cells[17], adult baboons, or patients with sickle cell anemia[18]. 2 CHEBI:15740 activates IP:IPR000971 IP:IPR000971 Chemical f31ee52c-5caf-11e7-af4d-001a4ae51247 PMC4667977 The agents tested included MS275 (Etinostat), a class I HDAC inhibitor of the benzamide family; SB939 (Pracinostat), a pan-HDAC inhibitor of the hydroxamic acid family; sodium dimethylbutyrate (SDMB), a short-chain fatty acid derivative which induces the fetal globin promoter but is not a pan-HDAC inhibitor; and Benserazide, a therapeutic approved for another medical condition for activity is as a dopa decarboxylase inhibitor, recently identified as a potent inducer of fetal globin (Perrine, submitted). 2 UNIPROT:O00767 activates IP:IPR000971 IP:IPR000971 Protein 7ef1934a-cb69-11ee-b346-0050569a791b 10.1016/j.mpaic.2015.11.007 In SCD, a mutation on chromosome 11 results in an amino acid substitution in which glutamic acid is replaced by valine to produce the abnormal β globin chain of haemoglobin S (HbS). 2 UNIPROT:P57682 increases IP:IPR000971 IP:IPR000971 Protein 32add0f2-c465-11e5-a92e-001a4ae51246 PMC3811682 "During erythroid differentiation, the decrease in the levels of KLF3 originating from the miR-23a upregulation prevented the recruitment of the CtBP corepressor and blocked KLF3 association with chromatin-modifying enzymes (25), which are required to further activate the expression of β-like globin genes." 2 PUBCHEM:455658 increases IP:IPR000971 IP:IPR000971 Chemical 5ce93638-bc07-11e5-8abe-001a4ae51246 10.1016/j.bbaexp.2004.03.003 Even with the induction of globin gene expression by haemin, no significant changes in the footprint pattern were observed. 2 UNIPROT:Q12905 activates IP:IPR000971 IP:IPR000971 Protein 28c6d2a4-c47f-11e5-8491-001a4ae51247 PMC2957209 In addition, knockdown of ILF2 in MEL cells produced significant reduction in mRNA of adult β‐major and β‐minor globin as well as α‐globin seen by RT–PCR (Figure 5B;Supplementary Figure 3). 2 UNIPROT:P13056 increases IP:IPR000971 IP:IPR000971 Protein a547d308-ee1b-11e5-872c-001a4ae51246 PMC4342359 TR2/TR4 combined loss reactivates embryonic and fetal globin gene expression To investigate the effects of compoundTr2andTr4loss of function on globin gene expression during adult erythropoiesis,Tr2−/−mice were interbred withTr4floxed (Tr4f/f) mice to finally generateTr2−/−:Tr4f/fcompound mutants (Figure 3A). 2 UNIPROT:Q9UNIPROTQ4 inhibits IP:IPR000971 IP:IPR000971 Protein 70cd99ae-c8e7-11e5-a1fd-001a4ae51246 18063753 Hls5 was originally isolated as a gene up-regulated during an erythroid-to-myeloid lineage switch,4and independently as a proapoptotic gene activated during macrophage maturation.21The suppression of GATA-1 activity by Hls5 could potentially promote maturation along the myeloid pathway, as inhibition of GATA-1 favors myelopoiesis over erythropoiesis.22Collectively, these data suggest that during the J2E erythroid/myeloid lineage switch, spontaneous activation of Hls5 suppresses globin synthesis, while Hls7/Mlf1 contributes to the altered morphology of the cells. 2 UNIPROT:P20073 inhibits IP:IPR000971 IP:IPR000971 Protein fd5df2b2-c8e5-11e5-a1fd-001a4ae51246 PMC1975097 The performance of the expression analysis using GeneChip U133 plus 2.0 was highly dependent on the addition of globin-blocking reagent SnX to the labeling reaction. 2 UNIPROT:P05231 increases IP:IPR000971 IP:IPR000971 Protein 7d22a376-0d06-11f0-a2ca-0050569a1f61 10.1016/S0145-2126(99)00141-1 It has been demonstrated that IL-6 also inhibited the mRNA and protein biosynthesis of the erythroid-specific gene γ globin in K562 cells, and decreased the γ and β globin mRNA expression in primary erythroid progenitor cells[34]. 2 UNIPROT:Q04206 inhibits IP:IPR000971 IP:IPR000971 Protein f5e45578-bbd2-11e5-8abe-001a4ae51246 10.1016/j.canlet.2005.09.014 Furthermore, dominant negative IkBα blocked TNFα- and NF-κBp65-mediated suppression of α-like globin promoter activity[9]. 2 FPLX:BMP increases IP:IPR000971 IP:IPR000971 ProteinFamily 895d8bda-cbf0-11e5-a19a-001a4ae51247 10556058 Cell autonomous inhibition of BMP activity in epidermis with dominant negative ligand dramatically reduced the amount of (&agr;)T3 globin expression. 2 UNIPROT:P14210 activates IP:IPR000971 IP:IPR000971 Protein ceb914b8-c9fe-11e5-b88f-001a4ae51247 14701703 GATA-1 was detected by in situ hybridization in the VBI in the late neurula, and expression was increased in the VBI as the blood island forms.8GATA-2 and SCL were expressed in both the VBI and DLP,2while GATA-3 was expressed in the DLP, but not the VBI.9In addition, it was shown that overexpression of SCL, GATA-1, or GATA-2 leads to increased globin production.10-12 Hepatocyte growth factor (HGF) was originally identified as a mitogen for hepatocytes and a motility enhancing factor for epithelial cells.13,14During mouse development, HGF and c-met were expressed in a wide variety of developing organs,15and were shown to play multiple roles as a mitogen, a motogen, and a morphogen in the organization of multicellular structures.16InXenopus,the HGF/c-met system was also shown to play a crucial role in liver development and structures of the pronephros at the late stage of development.17In addition, it was also reported that HGF was expressed in the early mesoderm region, especially in the ventral mesoderm, where primitive hematopoiesis occurs.18Although these data suggested that the HGF signaling pathway might also play a role in regulating hematopoiesis, none of our data revealed a function of HGF or c-met in blood differentiation. 2 UNIPROT:Q92793 actelytatesProtein IP:IPR000971 IP:IPR000971 Protein 56f6c22a-ca00-11e5-ab20-001a4ae51246 15273251 In this regard, NF-E4 is unlike several of the other erythroid transcription factors that bind to the globin locus, including GATA-1, EKLF, and p45 NF-E2, all of which are acetylated by CBP (10–12,38). 2 UNIPROT:Q92793 increases IP:IPR000971 IP:IPR000971 Protein 3b2e6234-ca5d-11e5-9088-001a4ae51247 12920040 Note added at proofs:Experiments performed since this manuscript was submitted, in which the CBP expression construct was driven by a more powerful promoter (CMV-CBP, kindness of Dr. Jenny Ting), show a modest up-regulation of EKLF-driven expression of the embryonic murine globin gene promoter by CBP, as previously reported at the adult β-globin gene.26As with p300 in the current manuscript, SCFAs further augment CBP with EKLF-driven expression from a murine embryonic globin gene promoter, at up to 2- to 5-fold. 2 IP:IPR006361 increases IP:IPR000971 IP:IPR000971 ProteinFamily 22b532b2-3407-11e8-bf76-001a4a160175 28483400 Both isoforms are directly associated with the differentiation of erythroblasts, since the correct amount of heme in the cytosol stimulates the overexpression of globin genes to form hemoglobin. 2 IP:IPR006361 increases IP:IPR000971 IP:IPR000971 ProteinFamily 0368f4ce-0e67-11f0-b759-0050569a791b 10.1182/blood.V91.3.798 Because the extent of a decrease in β-major globin synthesis was far greater than that of a decrease in its mRNA level, it is also possible that there is an additional posttranscriptional effect in globin synthesis due to heme deficiency, which may decrease the steady state level of β-major globin mRNA in ALAS-E(-) EBs. 2 IP:IPR006361 inhibits IP:IPR000971 IP:IPR000971 ProteinFamily 5d6fd3d6-bc4e-11e5-8d2d-001a4ae51247 PMC3079059 For example it is intimately involved in the regulation of erythropoiesis, regulating erythroid gene transcription—e.g., nuclear heme inhibits repression of the globin locus by the transcription factor Bach1, likely through direct binding[8]; erythroid gene translation, through inhibition of an erythroid-specific eIF-2α kinase (HRI) that regulates protein, especially globin translation[9,10]; and heme synthesis protein targeting and stability[11,12]. 2 IP:IPR006361 activates IP:IPR000971 IP:IPR000971 ProteinFamily e14dfbfe-bc14-11e5-8abe-001a4ae51246 10.1016/j.mod.2004.03.030 Blood cells in thewhomutant had little hemoglobin activity, suggesting that synthesis of globin and/or heme may have been impaired. 2 IP:IPR001519 inhibits IP:IPR000971 IP:IPR000971 ProteinFamily 539f1bf0-2c88-11f0-b759-0050569a791b 10.1182/blood.V99.10.3505 Using gel mobility shift assays in K562 erythroleukemic cells, Broyles and coworkers demonstrated specific binding of a protein with properties of ferritin H to a conserved CAGTGC motif in the beta globin promoter.135Transient transfection assays revealed that ferritin H repressed synthesis of beta globin, suggesting that ferritin may play a role in hemoglobin switching. 2 CHEBI:30772 decreases IP:IPR000971 IP:IPR000971 Chemical b1d950f0-d26f-11e5-85cd-001a4ae51247 PMC368526 Butyric acid, a modest inducer of murine erythroleukemia cells, induced a somewhat lower level of globin gene transcription. 2 CHEBI:30772 increases IP:IPR000971 IP:IPR000971 Chemical 82667f26-d038-11ee-b346-0050569a791b 10.1016/j.jds.2011.09.008 An intravenous infusion of butyric acid into patients with SCD drives the anemia into remission by downregulating sickle globin gene expression and upregulating fetal globin gene expression. 2 CHEBI:30772 increases IP:IPR000971 IP:IPR000971 Chemical 0725068c-bc52-11e5-9b9d-001a4ae51247 10.1016/j.leukres.2007.01.019 Similar functional differences between HDAC inhibitors have been described for non-malignant hematopoietic cells[29,30]: butyric acid increased γ globin mRNA levels in burst forming unit-erythroid colonies whereas TSA yielded drastic decreases in both β and γ globin. 2 MESH:D009190 activates IP:IPR000971 IP:IPR000971 Phenotype a5bea764-4558-11f0-b8fe-0050569a1f61 PMC9185154 A unifying pathophysiologic concept was introduced by our group several years ago.3We hypothesized that the anemia in DBA, as well as in del(5q) myelodysplastic syndrome (MDS) phenocopying DBA with an acquired loss of RPS14, is due to slowed globin chain synthesis and secondary heme toxicity. 2 CHEBI:17968 increases IP:IPR000971 IP:IPR000971 Chemical 0831b182-bbf9-11e5-9b9d-001a4ae51247 10.1016/S1079-9796(03)00024-X Other studies showed that butyrate and α-aminobutyric acid induce γ globin gene expression in adult baboons[2,3]. 2 CHEBI:17968 increases IP:IPR000971 IP:IPR000971 Chemical f0ca60bc-d9b2-11ee-9133-0050569a1f61 10.1016/S0301-472X(98)00010-1 In particular, hydroxyurea and butyrate both have been shown to raise fetal globin levels in cultured erythroid progenitors[7–9]. 2 MESH:D051379 activates IP:IPR000971 IP:IPR000971 Phenotype 0ed3a426-bc1e-11e5-9b9d-001a4ae51247 10.1016/j.jchromb.2009.06.013 Since mice with the Hbaahaplotype produce the same alpha globin (α1) at each alpha globin locus, C57 and 129 mice produce αβ dimers with different beta globins but identical alpha globins. 2 MESH:D051379 activates IP:IPR000971 IP:IPR000971 Phenotype df2c38fe-935e-11e7-82ff-001a4ae51246 12498775 Various hypotheses may account for the differences observed in terms of HbF reactivation between primates under acute stress conditions who increase HbF in response to rHuEpo, primates in chronic erythroid expansion who do not, and mice that increase β-min globin synthesis under both acute and chronic stimulation by an endogenous source of Epo. 2 UNIPROT:P01375 inhibits IP:IPR000971 IP:IPR000971 Protein f5e45578-bbd2-11e5-8abe-001a4ae51246 10.1016/j.canlet.2005.09.014 Furthermore, dominant negative IkBα blocked TNFα- and NF-κBp65-mediated suppression of α-like globin promoter activity[9]. 2 UNIPROT:P01579 increases IP:IPR000971 IP:IPR000971 Protein 143a36b8-c467-11e5-a92e-001a4ae51246 24336657 These results suggested that the suppression of the activin A induction of globin expression by IFN-γ may occur through two mechanisms: c-Jun inhibits NF-E2 transcriptional activity and c-Jun reduces NF-E2 through GATA-1. 2 MESH:D008024 inhibits IP:IPR000971 IP:IPR000971 Phenotype 28e39476-bc4f-11e5-8d2d-001a4ae51247 10.1016/j.meatsci.2004.06.007 The reaction between MbFe(III) and ONOO−yielded significantly less of the marker of nitrosative stress, 3-nitrotyrosine, in the globin moiety as compared to either apomyoglobin or cyanomyoglobin in which the heme is missing or blocked by a strong ligand, respectively (Herold, Shivashankar, & Mehl, 2002). 2 UNIPROT:Q99717 inhibits IP:IPR000971 IP:IPR000971 Protein 40293c72-c8e7-11e5-a1fd-001a4ae51246 PMC2200801 Liu et al14found that Smad5 is required to block induction of globin mRNA and effectively inhibit hematopoietic progenitor growth in day-4 embryoid body cultures treated with TGFβ1. 2 UNIPROT:P12644 inhibits IP:IPR000971 IP:IPR000971 Protein 12ef69c4-c8de-11e5-a1fd-001a4ae51246 16908518 We next coexpressed the MOs with BMP4 and discovered that both Smad4α-MO and Smad4β-MO blocked the induction of globin by BMP4 (Fig. 4C,lanes 5-7). 2 IP:IPR000971 activates IP:IPR000971 IP:IPR000971 ProteinFamily 007bc562-c46a-11e5-8491-001a4ae51247 24511086 Moreover, the observed decrease of globin protein levels in differentiated MELHO-1 cells (Figure 2C-D) further supports the conclusion that activated HRI inhibited globin translation. 2 IP:IPR000971 decreases IP:IPR000971 IP:IPR000971 ProteinFamily 2f19023e-377e-11e8-87fd-001a4a160176 10582345 Thus it is possible that the excess of foetal globin results from the inability of the residual BKLF to repress foetal globin transcription. 2 IP:IPR000971 activates IP:IPR000971 IP:IPR000971 ProteinFamily 757cf550-bc3d-11e5-8d2d-001a4ae51247 PMC1907364 KLF13 was cloned as a candidatetrans-activator of γ globin expression.14KLF13 activates γ globin promoter activity under transient transfection assays.14,15However, no change in endogenous γ globin gene expression was observed when KLF13 was silenced in K562 cells using RNAi. 2 IP:IPR000971 activates IP:IPR000971 IP:IPR000971 ProteinFamily 57fc359c-cc76-11e5-b6ad-001a4ae51246 9242673 The level of globin gene expression in E progenitor cells during lineage commitment is modulated directly by cell-specific transcription factors that bind to specific motifs in the locus control region and proximal globin gene promoters. 2 MESH:D006427 increases IP:IPR000971 IP:IPR000971 Phenotype d48fee66-3946-11e8-87fd-001a4a160176 15135653 In K562 cells, hemin has been shown to induce the expression of globin genes, the synthesis of hemoglobin and total RNA synthesis(Rutherford and Weatherall, 1979; Baliga et al., 1993; Bianchi et al., 2000). 2 MESH:D006427 activates IP:IPR000971 IP:IPR000971 Phenotype d48fee66-3946-11e8-87fd-001a4a160176 15135653 The action of hemin has been shown to stimulate the translation of globin mRNA in intact reticulocytes and in Friend erythroleukemic cells(Burns and London, 1965; Ross and Sautner, 1976). 2 MESH:D006427 activates IP:IPR000971 IP:IPR000971 Phenotype 06e68754-d3bd-11e5-b6ad-001a4ae51246 PMC411709 Rather, hemin, alone or in combination with dimethyl sulfoxide, induces accumulation of globin mRNA and nuclear globin RNA sequences. 2 UNIPROT:O43524 decreases IP:IPR000971 IP:IPR000971 Protein cf64e8e2-bbf3-11e5-9b9d-001a4ae51247 PMC4151266 Foxo3 is required for the regulation of oxidative stress in erythropoiesis in mice[25]and Foxo3 knockdown in K562 and TF-1 cells led to a striking reduction in globin expression (unpublished data). 2 UNIPROT:Q9H0D6 activates IP:IPR000971 IP:IPR000971 Protein 0cd07b82-bbfa-11e5-9b9d-001a4ae51247 10.1016/j.molcel.2005.11.002 Depletion of the homologous protein Xrn2 from human cells also impairs termination on a transiently transfected β globin gene (West et al., 2004). 2 MESH:D008288 inhibits IP:IPR000971 IP:IPR000971 Phenotype 1c7efe58-bc4c-11e5-ac4e-001a4ae51246 10.1016/j.exppara.2006.05.002 In conclusion, our results suggest that dequalinium could be a potential drug for the treatment of malaria, inhibiting both β-hematin synthesis and globin proteolysis. 2 MESH:D008697 decreases IP:IPR000971 IP:IPR000971 Phenotype 12ef69c4-c8de-11e5-a1fd-001a4ae51246 16908518 6C, both Smad4α-MO and Smad4β-MO greatly reduced the level of globin transcripts, suggesting that blood formation is sensitive to the levels of Smad4s. 2 UNIPROT:P02730 inhibits IP:IPR000971 IP:IPR000971 Protein 11898d48-0c78-11f0-aa93-0050569a1f61 10.1016/S0305-0491(00)00218-2 Reversed phase high-performance chromatography Globin chain separation followed essentially the reversed-phase HPLC (RP-HPLC) according toManca et al. (1990), Di Luccia et al. (1991b), for the study ofBovidaeglobin chains. 2 FPLX:HIF inhibits IP:IPR000971 IP:IPR000971 ProteinFamily 9a03b132-c9ff-11e5-be63-001a4ae51246 15169765 Moreover, since transiently expressed svSima was able to antagonize HIF-driven suppression (globin and Mt2) far better than induction (lactate dehydrogenase and CG11652), the data presented inFig. 2 FPLX:HIF activates IP:IPR000971 IP:IPR000971 ProteinFamily 9a03b132-c9ff-11e5-be63-001a4ae51246 15169765 We next addressed whether SL2 HIF mediates the hypoxic down-regulation of globin, which would, if true, represent the first description of a transinactivator role conferred by an invertebrate HIF. 2 UNIPROT:P15976 activates IP:IPR000971 IP:IPR000971 Protein 1197402e-bbfa-11e5-9b9d-001a4ae51247 PMC2807411 RT-PCR analysis revealed that GATA-1 and GATA-1(K137R) induced globin and xGATA-1 similarly. 2 UNIPROT:P15976 increases IP:IPR000971 IP:IPR000971 Protein 70cd99ae-c8e7-11e5-a1fd-001a4ae51246 18063753 The biologic consequences of elevated Hls5 in erythroid cells, viz severely impaired globin synthesis and restricted cell growth (Figure 1F-I), are consistent with Hls5 inhibiting the activity of GATA-1, because GATA-1 regulates globin gene transcription and cell cycle progression.15,16Hls5 might, therefore, play an important role in the maturation of red blood cells by modulating GATA-1 activity and expression of lineage-restricted functional genes.9,12–14,17The presence of numerous GATA binding sites in the Hls5 promoter,4adds another potential layer of cross-regulation between these molecules. 2 UNIPROT:P15976 activates IP:IPR000971 IP:IPR000971 Protein d4938ab2-eda3-11e5-872c-001a4ae51246 PMC4788764 In erythroid cells, GATA-1 activates heme biosynthetic genes, globin subunits, and constituents of the red cell cytoskeleton (Cheng et al., 2009; Fujiwara et al., 2009; Welch et al., 2004; Yu et al., 2009), all required for erythroid maturation. 2 UNIPROT:P15976 inhibits IP:IPR000971 IP:IPR000971 Protein 70cd99ae-c8e7-11e5-a1fd-001a4ae51246 18063753 Hls5, therefore, had a significant effect on globin synthesis and hemoglobin production, which could be caused, in part, by reduced GATA-1 levels.11However, the elimination of globin proteins indicates that post-transcriptional factors also influence globin content in J-Hls5 cells (Figure 1J). 2 UNIPROT:Q9BQI3 activates IP:IPR000971 IP:IPR000971 Protein 95f8c744-04ec-11f0-bb39-0050569a791b 10.1016/j.cmet.2024.07.022 Long ago, it was found that the addition of heme stimulated the synthesis of globin in reticulocytes extracts.65After outstanding biochemical work, the first eIF2α kinase, HRI, was identified.66Regulation of globin mRNA translation, to match iron levels, is now well understood.67The key factor is represented by HRI kinase, whose activation in conditions of heme deficiency reduces globin mRNA translation through eIF2α phosphorylation. 2 CHEBI:95074 increases IP:IPR000971 IP:IPR000971 Chemical e4e286d6-c475-11e5-85e4-001a4ae51246 PMC4608240 Similarly, we showed that UNC0638 treatment andEhmt2CRISPR/Cas9-mediated knockout in the murine cell line MEL increased the expression of bothHbb-εyandHbb-βh1embryonic globin genes. 2 FPLX:Hemoglobin activates IP:IPR000971 IP:IPR000971 ProteinFamily 58933388-2cf8-11f0-b759-0050569a791b 10.1182/blood.V97.12.3776 When injected into β-thalassemic mice, rhEpo has been shown to restore balanced globin chain synthesis and to improve the erythrocyte phenotype.10In patients with β-thalassemia, serum Epo levels are often lower than expected,11and injections of high doses of rhEpo have been shown to increase blood hemoglobin levels and occasionally to alleviate the need for transfusion.12–15 Although high doses of Epo may be beneficial for patients with β-thalassemia, the cost of such a treatment prevents its use in long-term controlled therapeutic trials and in routine clinical practice. 2 MESH:D000740 activates IP:IPR000971 IP:IPR000971 Phenotype a5bea764-4558-11f0-b8fe-0050569a1f61 PMC9185154 A unifying pathophysiologic concept was introduced by our group several years ago.3We hypothesized that the anemia in DBA, as well as in del(5q) myelodysplastic syndrome (MDS) phenocopying DBA with an acquired loss of RPS14, is due to slowed globin chain synthesis and secondary heme toxicity. 2 MESH:D001374 activates IP:IPR000971 IP:IPR000971 Phenotype 68d2fa08-c466-11e5-a92e-001a4ae51246 PMC3587326 Just as it has been shown that gene silencing may precede methylation, removal of 5-methylcytosine residues may often be necessary but not sufficient for gene reactivation (because other modifications, such as nucleosomal remodeling and histone methylation42,43,45,46may also be critical).44,46Indeed, it was shown more than 30 years ago that 5-azacytidine reactivates theHBGgene (γ globin) in erythroid cells, but notHBE(ϵ globin), although the 2 genes are only 15 kb apart, and display similar levels of hypomethylation after 5-AZA treatment. 2 UNIPROT:P61006 decreases IP:IPR000971 IP:IPR000971 Protein e4e286d6-c475-11e5-85e4-001a4ae51246 PMC4608240 Similarly, we showed that UNC0638 treatment andEhmt2CRISPR/Cas9-mediated knockout in the murine cell line MEL increased the expression of bothHbb-εyandHbb-βh1embryonic globin genes. 2 FPLX:FGF decreases IP:IPR000971 IP:IPR000971 ProteinFamily f8fdae18-c8dd-11e5-9ad8-001a4ae51247 16888091 A reduction of 4- to 5-fold in Gata1 expression was shown to markedly impair erythroid cell maturation in mice.79In our analyses, FGF strongly inhibits globin gene expression, although the cells surrounding FGF beads still express weak but detectable levels of Gata1. 2 UNIPROT:O43776 decreases IP:IPR000971 IP:IPR000971 Protein a547d308-ee1b-11e5-872c-001a4ae51246 PMC4342359 Hence, the combined loss of both NRs in adult erythroid cells led to induced embryonic globin transcript levels, in continuing support of a role for TR2/TR4 as an adult-stage repressor of the embryonic globin genes. 2 MESH:D006877 increases IP:IPR000971 IP:IPR000971 Phenotype 3ac895a8-ca5d-11e5-a3f7-001a4ae51246 PMC2808412 We have previously shown that hydroxamic acid derivatives of butyrate and propionate are strong γ gene inducers and exert their effects in concentrations that are almost 1 order of magnitude lower than those of the parent compounds.7Two other hydroxamic acid derivatives, SAHA and SBHA, induce γ globin gene expression in concentrations that are approximately 2 orders of magnitude lower than those of butyrate and propionate.7Here, we report induction of γ gene expression by 3 classes of HDAC inhibitors: analogues of trichostatin A, analogues of trapoxin, and scriptaid and its analogues. 2 UNIPROT:P35712 inhibits IP:IPR000971 IP:IPR000971 Protein aeab8cea-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2006.11.009 This extends our previous finding that Sox6 represses εy globin in early definitive erythropoiesis in the embryonic liver[20]. 2 UNIPROT:O95600 inhibits IP:IPR000971 IP:IPR000971 Protein 757cf550-bc3d-11e5-8d2d-001a4ae51247 PMC1907364 It has been reported that KLF8 inhibits γ globin promoter activity through the CACCC box using a transient transfection assay.11KLF8 has been shown to repress transcription by binding the CACCC box in association with the transcription repressor CtBP.12Together with our results using RNAi, it is suggested the KLF8 may play a negative role in γ globin expression. 2 UNIPROT:J3F2B0 increases IP:IPR000971 IP:IPR000971 Protein e4e286d6-c475-11e5-85e4-001a4ae51246 PMC4608240 Similarly, we showed that UNC0638 treatment andEhmt2CRISPR/Cas9-mediated knockout in the murine cell line MEL increased the expression of bothHbb-εyandHbb-βh1embryonic globin genes. 2 CHEBI:33709 activates IP:IPR000971 IP:IPR000971 Chemical 7ef1934a-cb69-11ee-b346-0050569a791b 10.1016/j.mpaic.2015.11.007 In SCD, a mutation on chromosome 11 results in an amino acid substitution in which glutamic acid is replaced by valine to produce the abnormal β globin chain of haemoglobin S (HbS). 2 UNIPROT:B1AH88 decreases IP:IPR000971 IP:IPR000971 Protein 672a6910-c476-11e5-a92e-001a4ae51246 PMC4722442 InGallus gallus, pharmacological binding of TSPO using PK11195 decreased globin levels indicating a function in the regulation of heme availability for the assembly of functional hemoglobin (25). 2 UNIPROT:Q9NZD4 increases IP:IPR000971 IP:IPR000971 Protein 266bcfb8-c471-11e5-a92e-001a4ae51246 PMC2700329 In agreement with our findings inE coli, both AHSP mutants Q25K and D29R enhanced α globin K99E expression in MEL cells. 2 UNIPROT:P04083 decreases IP:IPR000971 IP:IPR000971 Protein 29c5e258-bc00-11e5-9b9d-001a4ae51247 10.1016/j.bbrc.2005.04.049 A modest increase of the hemin-induced K562 cell differentiation by annexin1 overexpression and a significant inhibition of the differentiation by the annexin1 expression repression are evidenced by several aspects, including expression of differentiation makers, benzidine staining and globin quantification. 2 UNIPROT:P43034 activates IP:IPR000971 IP:IPR000971 Protein a5bea764-4558-11f0-b8fe-0050569a1f61 PMC9185154 A unifying pathophysiologic concept was introduced by our group several years ago.3We hypothesized that the anemia in DBA, as well as in del(5q) myelodysplastic syndrome (MDS) phenocopying DBA with an acquired loss of RPS14, is due to slowed globin chain synthesis and secondary heme toxicity. 2 UNIPROT:P31483 decreases IP:IPR000971 IP:IPR000971 Protein f5eeabb6-c8e5-11e5-9cb8-001a4ae51247 17711853 We next determined whether tethering of TIA-1 reduces the expression of globin mRNA or protein. 2 UNIPROT:O95936 activates IP:IPR000971 IP:IPR000971 Protein 2d335c9a-0ca0-11f0-b759-0050569a791b 10.1016/S0925-4773(00)00300-2 The Eomes promoter can be used to drive a heterologous globin reporter gene To test whether theEomes5′ flanking genomic sequence could be used to drive the expression of a heterologous reporter gene, we fused the 8.5 kbEomespromoter 5′ to the coding region of the humanβ-globingene, which starts at the globin initiator methionine and includes all threeβ-globinexons (Fig. 2A, top diagram) (Mohun et al., 1989; Howell and Hill, 1997). 2 UNIPROT:P14317 increases IP:IPR000971 IP:IPR000971 Protein 07819cc0-bbf9-11e5-9b9d-001a4ae51247 PMC1934938 Early experiments indicated that: (1) α-globin was not expressed in a 5′HS1-α-globin transgenic mouse[57]; (2) 5′HS1 contributed to full expression within the context of the LCR, but only low expression was observed when just 5′HS1 was present to drive globin gene expression[58]; and (3) LCR 5′HS1 was not important for adult globin gene expression[11]. 2 UNIPROT:P14317 increases IP:IPR000971 IP:IPR000971 Protein 6eee350c-c8e8-11e5-9cb8-001a4ae51247 PMC2234778 This fits with results of Pasceri et al,21who found that HS1 enhanced LCR-dependent globin expression in nonviral constructs tested in transgenic mice. 2 CHEBI:9433 inhibits IP:IPR000971 IP:IPR000971 Chemical e45bb570-efb4-11ee-8b99-0050569a1f61 10.1016/j.toxlet.2003.12.008 The down-regulation of mRNA expression for γ-globin and PBGD genes induced by tellimagrandin I in BA-induced K562 cells indicated that tellimagrandin I inhibited heme and globin synthesis at transcriptional level, leading to inhibition of hemoglobin synthesis. 2 UNIPROT:P22557 activates IP:IPR000971 IP:IPR000971 Protein 0368f4ce-0e67-11f0-b759-0050569a791b 10.1182/blood.V91.3.798 The significance of heme deficiency in β-major globin synthesis is also corroborated by the fact that globin protein synthesis was partially restored by treatment of ALAS-E(-) ES cells with exogenous ALA. 2 CHEBI:17968 activates IP:IPR000971 IP:IPR000971 Chemical 0d35c498-bbf9-11e5-9b9d-001a4ae51247 10.1016/j.bcmd.2010.10.013 Proposed molecular mechanisms of butyrate-mediated globin gene regulation include induced cell signaling and epigenetic modifications, with a recent focus on butyrate-mediated stimulation of stress erythropoiesis and p38 phosphorylation[5,6,19].|||As in K562 cells and human CD34-derived EryD, p38 inhibitors block butyrate-mediated fetal/embryonic globin gene induction in FL EryD. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P02144 Protein c4a153e8-c47f-11e5-85e4-001a4ae51246 PMC2911317 Globin Reduction Assays Reduction of ferric Cygb, Ngb, and Mb was measured by following the formation of the ferrous-CO complex at 422, 416, and 422 nm, respectively, in a 1-cm thermostatted quartz cuvette at 37 °C. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P02144 Protein 25c4096a-bc4f-11e5-ac4e-001a4ae51246 10.1016/S0309-1740(02)00032-3 The unfolding of the globin moiety allows much easier myoglobin autoxidation and more difficult MetMb reduction. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P00966 Protein 07761dee-3917-11e8-8f56-001a4a160175 24467927 In other words, a daily exposure of G at 0.60μg/kg bw would result in 1pmol/g globin increase of steady-state level (Ass) of diHOPrVal. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P0A3H1 Protein 7cacde70-c914-11ee-9aaa-0050569a1f61 PMC9979759 The single point genetic mutation in the beta chain of globin (Glu6Val) causes the production of abnormal Hb (HbS) in sickle RBCs. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P0A3H1 Protein e4411476-3904-11e8-a34b-001a4a160175 28735981 Sickle-cell disease (SCD) is caused by an autosomal recessive mutation of theHBB(beta globin) gene leading to abnormality of β-globin chain, hemoglobin S (HbS), which polymerizes when deoxygenated, resulting in deformed and rigid erythrocytes. 1 IP:IPR000971 IP:IPR000971 decreases UNIPROT:Q13351 Protein 1061aa92-bbf9-11e5-8abe-001a4ae51246 10.1016/j.bcmd.2011.10.003 During embryonic and fetal stage KLF1 levels are low resulting in low levels of adult beta globin, while in the adult high KLF1 expression induces elevated levels of adult beta globin and BCL11A, which in turn represses gamma globin expression[4,8,9]. 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:Q13351 Protein be5009ba-c8e6-11e5-9cb8-001a4ae51247 PMC1820495 "Also, overexpression of EKLF leads to increased transcription of the adult β globin gene and an earlier switch from fetal γ to adult β globin expression (33,53), while decreasing the concentration of EKLF results in lowered expression of β with a reciprocal increase in γ gene expression (58)." 1 IP:IPR000971 IP:IPR000971 increases UNIPROT:Q13351 Protein 1061aa92-bbf9-11e5-8abe-001a4ae51246 10.1016/j.bcmd.2011.10.003 During embryonic and fetal stage KLF1 levels are low resulting in low levels of adult beta globin, while in the adult high KLF1 expression induces elevated levels of adult beta globin and BCL11A, which in turn represses gamma globin expression[4,8,9]. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q13351 Protein 6e583cda-c8e0-11e5-9624-001a4ae51246 PMC1538551 As in ln2 HPC, GATA‐1 is not detected at HS2 or globin promoters in ln2 EKLF−/−HPC (Figure 2F). 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P29466 Protein 6e583cda-c8e0-11e5-9624-001a4ae51246 PMC1538551 Additionally, disruption of globin gene potentiation in ln2 p45−/−HPC is associated with a significant decrease in huβ‐gene expression in ln2 p45−/−EryC, which is, on average, three‐fold lower than in ln2 EryC (Supplementary Figure 8). 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P02042 Protein d0187326-bc34-11e5-ac4e-001a4ae51246 PMC2668177 Two other hemoglobin genes, HBD and HBE, were also significantly down-regulated by globin reduction in both assays. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P02042 Protein 4d09d836-d529-11e5-b811-001a4ae51247 PMC1213851 The globin products of Hbc and Hbd are electrophoretically indistinguishable; therefore, it is impossible to enumerate true gene frequencies in population surveys. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P06730 Protein 1bbadf0a-cb29-11e5-a6cd-001a4ae51247 11418588 eIF4B is a dimeric protein (70-kDa subunit) that has no independent catalytic activity and functions to stimulate the RNA binding, ATPase, and helicase activities of eIF4A and eIF4F, as well as overall globin synthesis in fractionated lysate systems (13,16-19). 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:Q01658 Protein 88411170-c8e6-11e5-a1fd-001a4ae51246 PMC1864974 We also examined a different transgenic line: mutDR has a 4 nt substitution in the Aγ‐globin gene promoter that specifically abolishes the DR1 element (Omoriet al, 2005); this mutation induced Aγ‐globin gene expression by six‐fold compared to the wild‐type YAC transgene (line 264). 1 IP:IPR000971 IP:IPR000971 increases UNIPROT:P81172 Protein e302610a-f540-11eb-bbfe-001a4a160176 29969719 Thalassemia is a group of hereditary anemias caused by mutations in globin genes, manifesting as ineffective erythropoiesis in the bone marrow and iron overload due to inappropriately low hepcidin expression[145,146]. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q9BZE4 Protein c4a153e8-c47f-11e5-85e4-001a4ae51246 PMC2911317 Globin Reduction Assays Reduction of ferric Cygb, Ngb, and Mb was measured by following the formation of the ferrous-CO complex at 422, 416, and 422 nm, respectively, in a 1-cm thermostatted quartz cuvette at 37 °C. 1 IP:IPR000971 IP:IPR000971 increases UNIPROT:Q9BZE4 Protein 15a414de-3aa2-11e8-bf76-001a4a160175 25683270 The recent discovery that E2 via ERβ signaling increases up to 300% the level of NGB[16,17], a globin involved in preventing apoptosis in neuroblastoma cell line, raised the possibility that NGB could regulate the ERβ activities shunning this receptor subtype to trigger an apoptotic cascade in neurons but not in colon cancer cells. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q01130 Protein 3a956c24-bc47-11e5-8d2d-001a4ae51247 PMC2063548 We did find that the globin genes had increased contact with SC35-positive nuclear speckles (Spector, 1993). 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P02100 Protein d0187326-bc34-11e5-ac4e-001a4ae51246 PMC2668177 Two other hemoglobin genes, HBD and HBE, were also significantly down-regulated by globin reduction in both assays. 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P09601 Protein 5c306e30-bc36-11e5-8d2d-001a4ae51247 PMC4624791 The observation that both heme addition and inhibition of HO increase globin expression in β-K562 is consistent with the expected role of heme in relieving translational inhibition by HRI; however, the increase of globin mRNA levels, particularly of γ-globin (mRNA and protein) is not easily explained only by a simple effect on globin mRNA translation. 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P09466 Protein 285d358c-ae94-11ec-8b2e-0050569a1f61 PMCPMC8661426 The globin depleted (GD) RNA was further purified by RNA binding beads and finally eluted in elution buffer. 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P09466 Protein 6fe52388-bc33-11e5-ac4e-001a4ae51246 PMC3946641 Comparison of the technical replicates under different treatments, either globin depleted (GD) or not (NGD), will allow us to assess technical variability associated with globin depletion and study differences in transcriptome profiles. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P39019 Protein 292e4b58-c468-11e5-91a7-001a4ae51247 PMC3648058 "Hence, it is proposed that delayed translation of globin mRNA results in a relative increase in free heme, causing oxidative stress and hemolysis of erythroid progenitors and producing the anemic phenotype in DBA (12,26)." 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P39019 Protein 603ecd50-bbe1-11e5-8abe-001a4ae51246 PMC4123107 This indicates that accumulative defects of protein production in erythroid cells probably contribute to the reduction of globin proteins, which leads to the blood-specific defects in DBA patients. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P31040 Protein 85359714-c470-11e5-9da3-001a4ae51247 PMC2764181 "Recently it has been proposed that an excess of denatured globin, caused by binding of CQ to FP, could contribute to the antimalarial activity of CQ by inhibiting endosomal maturation and ultimately FP crystallization (17)." 1 IP:IPR000971 IP:IPR000971 increases UNIPROT:Q9H165 Protein cfc5c4b8-c464-11e5-85e4-001a4ae51246 PMC3767509 SetD8 knockdown did not alter expression of the established repressor of embryonic/fetal β-like globin genesBcl11a, orKlf1, which can induce BCL11A expression (43) (Fig. 1E). 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P01033 Protein d61238b2-f598-11eb-90d3-001a4a160175 31170385 AChE in erythroblast leads to elevated EPO-induced globin expression In EPO-induced TF-1  1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P42575 Protein 0eb998f4-bc25-11e5-9b9d-001a4ae51247 PMC4013584 The protein encoded by this gene is a member of the globin molecule family with a double functional nature: antioxidant activity, inducing superoxide dismutase, and anti-apoptotic activity, inhibiting the apoptotic effects of caspase-2 and caspase-3 [149–152]. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q10992 Protein 8bb8b36c-bbfd-11e5-9b9d-001a4ae51247 PMC4485482 Sickle cell anaemia (SCA) is caused by a mutation in the β globin gene. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:O00767 Protein 5d0241cb-f576-11eb-8e7d-001a4a160176 32852615 SCD is caused by a missense mutation in the human beta globin gene (HBB) leading to the hemoglobin variant HbS. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:O00767 Protein cebbd356-c47c-11e5-91a7-001a4ae51247 21744494 SCD is caused by the inheritance of the sickle β globin gene (βS) and is the homozygous state (SS) when this gene is inherited from both parents. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:O00767 Protein 771f9ac2-bc22-11e5-8abe-001a4ae51246 PMC3407482 Homozygous expression of this mutant globin genotype (SS) causes SCD, while the heterozygous genotype (AS) is termed the “sickle cell trait” [1,2]. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:O00767 Protein 57905f2a-ca00-11e5-be63-001a4ae51246 15252187 Furthermore, forced expression of fetal globins, caused either by inhibition of fetal globin-gene silencing or by reactivation of expression in adult life decreases clinical severity in SCD (48). 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P13056 Protein 88411170-c8e6-11e5-a1fd-001a4ae51246 PMC1864974 TR2/TR4 as a target for therapeutic intervention in sickle‐cell disease Sickle‐cell disease is caused by a missense mutation in the adult β‐globin gene and affects millions of people worldwide (Stuart and Nagel, 2004). 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P69891 Protein 716dc062-394e-11e8-9fbf-001a4a160176 19922785 Selective globin genes and genes related with erythroid differentiation in APS-induced K562 cells The γ-globin gene (HBG1/HBG2), SLR was 2.1, meaning it was up-regulated 4.3-fold. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q8WWM9 Protein c4a153e8-c47f-11e5-85e4-001a4ae51246 PMC2911317 Globin Reduction Assays Reduction of ferric Cygb, Ngb, and Mb was measured by following the formation of the ferrous-CO complex at 422, 416, and 422 nm, respectively, in a 1-cm thermostatted quartz cuvette at 37 °C. 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:Q8NEJ9 Protein 6fe52388-bc33-11e5-ac4e-001a4ae51246 PMC3946641 Finally, we perform a limited differential gene expression analysis between globin depleted (GD) and non-globin depleted (NGD) samples in order to study any systematic effects of globin depletion on gene expression. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P10721 Protein ec466dea-c9ff-11e5-be63-001a4ae51246 14990860 In contrast, the TGF-β-treated cultures show not only a larger proportion of γ+cells, but also much higher levels of globin, confirming previous reports that TGF-β accelerates maturation [15,16], perhaps by downmodulating the c-kit receptor and thus interfering with the maturation-retarding effect of SCF [27–29]. 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P17947 Protein 71ed70b4-bc1e-11e5-9b9d-001a4ae51247 PMC3556575 Introduction The molecular network of genes involved in the development of erythroid cells has begun to be better understood for the past few years.1,2,3,4,5,6,7,8,9The underlying molecular mechanism of erythroid cellular differentiation is a complex process, which is subject to a number of physiological conditions.10,11,12,13,14,15,16,17Most importantly, erythroid differentiation is regulated by the erythroid transcription factor globin transcription factor (GATA)-1, which represses GATA-2 and PU.1 and impacts on early and late differentiation.18,19At the terminal stage of differentiation, the erythroid program is defined by the genes that are still expressed. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q13410 Protein c48f3a56-7b87-11ee-ae93-0050569a1f61 10.1007/s00404-023-07032-6 The absence or decreased production of hemoglobin tetramer beta globin chains causes beta thalassemia (BT). 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q2YIQ4 Protein 0d35c498-bbf9-11e5-9b9d-001a4ae51247 10.1016/j.bcmd.2010.10.013 Therefore, embryonic globin gene induction (βH1 and εY) in FL EryD serves as a surrogate for the up regulation of fetal β-type globin gene expression in human definitive erythroid cells. 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:O14867 Protein 03c49450-c8e9-11e5-a1fd-001a4ae51246 18258918 Heme also initiates globin transcription through inhibiting the DNA binding of the repressor, Bach1 (1), and globin translation through inhibiting substrate phosphorylation by the repressor, erythroid-specific eukaryotic initiation factor 2α kinase (2). 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:O14867 Protein eaa3ee78-c46d-11e5-91a7-001a4ae51247 PMC4040894 It has been reported that heme activates globin transcription by inhibiting the binding activity of BACH1 to the MARE sites in the locus control region of globin genes.52,53 In addition, heme also controls the transcription of other ubiquitously expressed genes, like the heme degrading enzyme heme-oxygenase-1,50the iron storage proteins Hand L-ferritin51and the iron exporter ferroportin.54The role of heme-oxygenase1 during erythroid differentiation is still controversial. 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:O14867 Protein a72985f6-ab4c-11e6-9ac8-001a4ae51246 PMC5010382 Heme then rapidly induces globin transcription and translation, by inhibiting repressors BACH1 (15,16) and heme-regulated eIF2α (eukaryotic initiation factor 2α) kinase (HRI) (17), respectively. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P49116 Protein 88411170-c8e6-11e5-a1fd-001a4ae51246 PMC1864974 TR2/TR4 as a target for therapeutic intervention in sickle‐cell disease Sickle‐cell disease is caused by a missense mutation in the adult β‐globin gene and affects millions of people worldwide (Stuart and Nagel, 2004). 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P70753 Protein 8c352c26-ca5d-11e5-9088-001a4ae51247 PMC156302 "Similar position effects have been observed on transgenes composed of globin regulatory elements driving the LacZ reporter (20) but never on normal globin genes." 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P70753 Protein 3611db2a-c8e9-11e5-9624-001a4ae51246 PMC2441975 "Thus, we have used recombinant HIV-1 Gag polyprotein that was added to translation assays programmed with different constructs including mRNAs in which LacZ production was driven by the Globin 5′-UTR or the EMCV IRES." 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q5HEN9 Protein 7380c418-ca00-11e5-be63-001a4ae51246 15254344 "Briefly, homozygous p53 null FVB/N (N10) male mice were intercrossed with homozygous p53 wild-type inbred FVB/N transgenic female Tg.AC mice hemizygous for the Tg.AC transgene (zeta globin promoted v-Ha-ras) to produce heterozygous p53 FVB/N progeny hemizygous for the transgene." 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:Q968Y9 Protein a3e37014-bbd8-11e5-8abe-001a4ae51246 PMC2228317 Adverse conditions for growth and reproduction (crowding, high temperature,...) lead to reduced DAF-2 signaling and increasing silencing of the HIF responsive globin promoters by the DAF-16 FOXO transcription factor. 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:Q9BQI3 Protein 62fbee56-c7a9-11ee-8b99-0050569a1f61 10.1016/j.aquaculture.2023.739525 Heme rapidly induces globin transcription and translation by removing Bach1 and inhibiting HRI activity(Doty et al., 2019). 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q9BQI3 Protein d0503556-cb28-11e5-a6cd-001a4ae51247 PMC125753 Quantitation of [35S]methionine incorporation into the globin chains showed that there was a 7‐fold increase in globin synthesis in HRI−/−reticulocytes as compared with HRI+/+reticulocytes (Figure 2D). 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P61006 Protein b716e576-cb8c-11e5-8106-001a4ae51247 PMC305797 To confirm further that NFE‐6 contains C/EBPγ, we cloned the cDNA by RT–PCR and expressed two versions of C/EBPγ under the control of the β‐globin promoter and locus control region (LCR) in MEL cells (Needhamet al., 1992). 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P61006 Protein 6984533c-bc48-11e5-9b9d-001a4ae51247 10.1016/j.jprot.2012.12.014 We found that Zfp445 was specifically recruited to the Ey globin gene promoter in uninduced MEL cells, as shown by ChIP results presented inFig. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P61006 Protein f41f0a90-c8e7-11e5-a1fd-001a4ae51246 PMC1852780 Interestingly, a recent report has shown that EKLF is recruited to the mouse α globin promoter in induced MEL cells (Shyuet al, 2006). 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:Q5T7V8 Protein 504af92e-bbf4-11e5-9b9d-001a4ae51247 PMC2890980 Globin-reduced samples were similarly enriched for GO biological processes and molecular functions (Supplementary Figs. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P28347 Protein c1cf8202-c484-11e5-a92e-001a4ae51246 PMC3401215 In addition, we used Townes mice that have both human α- and β- (βA and βS form) globin genes knocked into the mouse locus, allowing the generation of littermate AA and SS mice (here referred to as TWAAand TWSS) after intercrossing TWASmice.19The generation of TFflox/flox,Tie-2 Cre+ mice has been previously described.20All mouse experiments were approved by the University of North Carolina Animal Care and Use Committees and complied with National Institutes of Health guidelines. 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P29320 Protein bf826f96-ae93-11ec-b4ed-0050569a1f61 PMCPMC8363739 1CRISPR-Cas9-mediated globin gene targeting induces Chr11p terminal deletions in HEK cells.aExperimental design. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P08922 Protein 8efdd59a-dc96-11ea-8c8a-001a4a160176 PMC6168382 As a result, the intracellular ROS is significantly increased by exacerbated autoxidation of α globin leading to increased membrane-bound globin and consequent perturbation of erythrocyte structure[49,50]. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P08922 Protein deb6096a-c482-11e5-8491-001a4ae51247 PMC3369616 During chronic iron deficiency ofHri−/−mice, both reduced antioxidant gene expression (Figure 2and Liu et al23) and heme-free globin precipitates3probably contribute to the increased ROS levels inHri−/−erythroid cells. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q99578 Protein 6f4e2c9c-bc4e-11e5-8abe-001a4ae51246 PMC4239376 Furthermore, Mastrokolias et al. [25] also found that globin reduction led to a slight decrease in RIN values, as non-globin reduced samples had average RIN values of approximately 7.7, while those subject to globin reduction had average RIN values of 7.3. 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:Q99578 Protein 6f4e2c9c-bc4e-11e5-8abe-001a4ae51246 PMC4239376 Furthermore, Mastrokolias et al. [25] also found that globin reduction led to a slight decrease in RIN values, as non-globin reduced samples had average RIN values of approximately 7.7, while those subject to globin reduction had average RIN values of 7.3. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:Q9Y5K5 Protein 1e67de52-c47f-11e5-91a7-001a4ae51247 PMC3098602 This is congruent with the studies using purified proteasomes, but whether the globin-directed chain trimming activity in the extracts is in fact UCH37, rather than USP14, which is also inhibited by ubiquitin aldehyde, is unclear. 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P23769 Protein 71ed70b4-bc1e-11e5-9b9d-001a4ae51247 PMC3556575 Introduction The molecular network of genes involved in the development of erythroid cells has begun to be better understood for the past few years.1,2,3,4,5,6,7,8,9The underlying molecular mechanism of erythroid cellular differentiation is a complex process, which is subject to a number of physiological conditions.10,11,12,13,14,15,16,17Most importantly, erythroid differentiation is regulated by the erythroid transcription factor globin transcription factor (GATA)-1, which represses GATA-2 and PU.1 and impacts on early and late differentiation.18,19At the terminal stage of differentiation, the erythroid program is defined by the genes that are still expressed. 1 IP:IPR000971 IP:IPR000971 activates UNIPROT:P68871 Protein dba3c322-bc3d-11e5-9b9d-001a4ae51247 PMC4669122 The globin cluster LCR activates the gamma-globin gene during fetal development, and during adulthood, the LCR transitions to activate the beta-globin gene while gamma-globin is silenced. 1 IP:IPR000971 IP:IPR000971 inhibits UNIPROT:P22557 Protein 0368f4ce-0e67-11f0-b759-0050569a791b 10.1182/blood.V91.3.798 This question is particularly intriguing because globin mRNA translation is known to be regulated by the phosphorylation of the α-subunit of eukaryotic translation initiation factor (eIF-2α) by the heme-regulated eIF-2α kinase (HRI).8It is possible therefore that deficient heme synthesis may activate HRI and thus inhibit protein synthesis in ALAS-E–deficient erythroid cells. 1 IP:IPR000971 IP:IPR000971 inhibits PUBCHEM:53477764 Chemical 19c635ea-bc02-11e5-8abe-001a4ae51246 10.1016/j.foodchem.2010.06.028 The three important functions of the globin portion of myoglobin are to sequester haem, enhance coordination with the proximal histidine, and inhibit oxidation of the iron atom (Liong et al., 2001). 1 IP:IPR000971 IP:IPR000971 inhibits PUBCHEM:53477764 Chemical 4152033e-375a-11e8-9192-001a4a160175 29126700 This reaction is essentially blocked in haem proteins by the bulk of the globin protein, which prevents close approach of two haem moieties. 1 IP:IPR000971 IP:IPR000971 activates CHEBI:15841 Chemical 85ab8a86-d2bd-11e5-85cd-001a4ae51247 PMC369818 This polypeptide (beta') was synthesized by translational read-through of the beta- globin mRNA UGA terminator and was mediated primarily by an endogenous tRNA coded for by the mitochondria. 1 IP:IPR000971 IP:IPR000971 activates CHEBI:49468 Chemical 0d437548-c469-11e5-9da3-001a4ae51247 24139948 Imbalances of globin chains cause hemolysis, which results in mild to severe anemia.1Patients with anemia may have atrophic glossitis (AG) or generalized oral mucosal atrophy and tenderness or burning sensation of oral mucosa.2However, it is still not known whether patients with thalassemia trait (TT including α- or β-thalassemia minor) may have specific oral manifestations and what percentages of TT patients may have the oral manifestations. 1 IP:IPR000971 IP:IPR000971 inhibits CHEBI:32029 Chemical 7081aaca-c8e8-11e5-9cb8-001a4ae51247 17928589 Translation of globin mRNA by rabbit reticulocyte lysate in vitro is inhibited when osmolality is increased by adding NaCl, KCl, CH3CO2Na, or CH3CO2K, but not by adding the compatible osmolytes betaine ormyo-inositol (26). 1 IP:IPR000971 IP:IPR000971 inhibits CHEBI:18420 Chemical f9ce2482-f58e-11eb-95de-001a4a160176 30146452 In short, the isolated polyA RNA or rRNA/globin depleted RNA was Mg2+/heat fragmented (~200  1 IP:IPR000971 IP:IPR000971 activates CHEBI:33709 Chemical 61770e8a-c8e8-11e5-9624-001a4ae51246 17932132 "Structural Hb variants are typically due to a point mutation in a globin gene that produces a single amino acid substitution in a globin chain." 1 IP:IPR000971 IP:IPR000971 activates CHEBI:33709 Chemical 4ef8a072-ca5d-11e5-8050-001a4ae51246 14634026 InReaction 2, the porphyrin radical dissipates in the globin, causing formation of amino acid radicals while leaving the heme moiety in a FeIV=O form similar to compound II (5–8). 1 IP:IPR000971 IP:IPR000971 activates CHEBI:33709 Chemical 17527ad8-bbe6-11e5-9b9d-001a4ae51247 PMC4659689 Variants of the structural haemoglobin are based on a point mutation in a globin gene that produces a single amino acid substitution in a globin chain [8]. 1 IP:IPR000971 IP:IPR000971 activates CHEBI:33709 Chemical b96bc3fa-3755-11e8-bf76-001a4a160175 25943047 Structural haemoglobinopathies generally arise from point mutations in the globin genes that produce a single amino acid substitution in the globin chain[16]. 1 IP:IPR000971 IP:IPR000971 activates CHEBI:33709 Chemical ed2d9b54-bc1a-11e5-8abe-001a4ae51246 PMC4003441 In a few cases both phenotypes are observed with reduced synthesis of a hemoglobin variant such as Hb E. Structural variants of hemoglobin (Hb) typically are due to a point mutation in globin gene that produces a single amino acid substitution in the globin chain. 1 IP:IPR000971 IP:IPR000971 inhibits CHEBI:8337 Chemical bbac2d94-392b-11e8-bf76-001a4a160175 9268649 In the T-state α-subunits, the Fe atom moves into the plane of the porphyrin but the globin prevents the porphyrin from flattening and restricts the movement of the proximal histidine towards the haem. 1 IP:IPR000971 IP:IPR000971 activates MESH:D005978 Phenotype 81817ffa-bbe9-11e5-9b9d-001a4ae51247 PMC3202272 The enzyme system required globin chain synthesis; energy metabolism synthesis of glutathione should be taken as Raktagni. 1 IP:IPR000971 IP:IPR000971 activates GO:0006810 Phenotype ee599c11-7f6e-11ea-817d-001a4a160175 PMC2115535 Expression of Globin-related Proteins in GH3 Cells To test the hypothesis that the SRIF propeptide mediates in-traceUular transport, we expressed two chimeric proteins in GH3 cells: PRO-GLO, a fusion of the SRIF preproregion and chimpanzee c~-globin; and a control precursor, SIG-GLO, consisting of the/3-1actamase signal peptide fused to ct-globin ( Fig. 1 B) . 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D011189 Phenotype 7081aaca-c8e8-11e5-9cb8-001a4ae51247 17928589 Translation of globin mRNA by rabbit reticulocyte lysate in vitro is inhibited when osmolality is increased by adding NaCl, KCl, CH3CO2Na, or CH3CO2K, but not by adding the compatible osmolytes betaine ormyo-inositol (26). 1 IP:IPR000971 IP:IPR000971 activates MESH:D004194 Phenotype 1d6cb3e2-c8df-11e5-9cb8-001a4ae51247 16960127 Natural mutants of the globin genes underlie the most common inherited diseases throughout the world, the α- and β-thalassemias and sickle cell disease. 1 IP:IPR000971 IP:IPR000971 activates MESH:D004194 Phenotype 014143dc-c862-11ee-b346-0050569a791b 10.1016/j.transci.2022.103620 Introduction Thalassemia is comprised of a group of inherited diseases that are caused by a decrease or an absence of globin synthesis resulting in globin chain imbalance, abnormal red blood cell (RBC) morphology, and reduced RBC lifespan. 1 IP:IPR000971 IP:IPR000971 activates MESH:D004194 Phenotype 1430417e-c9ff-11e5-9b70-001a4ae51247 21706753 Hemoglobinopathies represent a large group of inherited diseases caused by mutations in α and β globin genes. 1 IP:IPR000971 IP:IPR000971 activates MESH:D004194 Phenotype 39085128-ea6a-11ee-b346-0050569a791b 10.1016/j.cca.2022.08.001 Introduction Thalassaemia is a group of abnormal haemoglobin diseases caused by hereditary disorders of globin chain synthesis. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0016458 Phenotype 81d74ac6-c47b-11e5-8491-001a4ae51247 PMC3147791 "These notions strongly suggest a functional significance of the TR2/TR4-DNMT1 interaction and recruitment of this complex to the embryonic globin promoters in gene silencing." 1 IP:IPR000971 IP:IPR000971 activates MESH:D002386 Phenotype 3009809a-c8ec-11e5-878b-001a4ae51247 PMC2652363 Examples include neurodegenerative disorders, cataracts, the major form of cystic fibrosis, and myopathies.19-22In the thalassemia syndromes, synthetic imbalance of globin chains leads to the formation of toxic protein precipitates in erythroid cells.23,24In this way, the thalassemias are largely disorders of unstable protein accumulation and, therefore, potentially subject to modulation by protein quality control pathways.In addition to interacting with denatured proteins, molecular chaperones bind many native folded proteins to modulate their cellular activities. 1 IP:IPR000971 IP:IPR000971 activates MESH:D000755 Phenotype 77357924-c473-11e5-8491-001a4ae51247 25696889 "Introduction Sickle cell anemia is one of the most common monogenic disorders in the world, affecting an estimated 1%–4% of newborns in sub-Saharan Africa1and ∼1 in 600 African Americans in the United States.2It is an autosomal-recessive Mendelian disease that is caused by a single point mutation in the beta globin gene.3This mutation results in the substitution of a glutamic acid residue with valine at position 6." 1 IP:IPR000971 IP:IPR000971 activates MESH:D000755 Phenotype 6bc77e36-c485-11e5-85e4-001a4ae51246 22362400 Inherited in the homozygous form, the beta globin gene mutation leads to sickle cell disease (SCD). 1 IP:IPR000971 IP:IPR000971 activates MESH:D017086 Phenotype 8efed8c0-b80d-11ee-bde4-0050569a1f61 PMC7042447 Beta-thalassemia is caused by the reduced (beta +) or absent (beta0) synthesis of the beta globin chains of the hemoglobin tetramer [13]. 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D017086 Phenotype c50b047a-c478-11e5-91a7-001a4ae51247 21558467 "Butyrate stimulates production of fetal hemoglobin through induction of the fetal (γ) globin gene promoter, which thereby reduces globin chain imbalance in beta thalassemia, which in turn reduces anemia, or inhibition of polymerization of sickle hemoglobin; both effects ameliorate the clinical courses of the respective disease conditions (Steinberg and Rodgers 2001;Perrine 2005)." 1 IP:IPR000971 IP:IPR000971 activates MESH:D017086 Phenotype 3f2338d2-c39b-11e6-9a62-001a4ae51246 PMC5121445 Beta-thalassemia is caused by the reduced (beta+) or absent (beta0) synthesis of the beta globin chains of the hemoglobin (Hb) tetramer, which is made up of two alpha globin and two beta globin chains (alpha2beta2) [1,2]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D017086 Phenotype 37e9f41a-340c-11e8-9fbf-001a4a160176 20098328 Beta-thalassemia is caused by the reduced (beta+) or absent (beta0) synthesis of the beta globin chains of the hemoglobin tetramer. 1 IP:IPR000971 IP:IPR000971 activates MESH:D017086 Phenotype b0e1dc82-bc1a-11e5-9b9d-001a4ae51247 PMC3065626 To date, more than 200 causative molecular defects have been described in the beta globin gene causing beta thalassemia [5-7]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D017086 Phenotype 608d41e4-ae95-11ec-8f68-0050569a1f61 PMCPMC8142798 This case describes SCC as a consequence of EMH presenting as a mass in presacral area.Beta thalassemia major is the severe form of beta thalassemia, which is caused by mutations in beta globin gene, either reduced (β ) or absent (β ) in hemoglobin A resulting in unbound α globin chains that accumulate in erythroid precursors in the bone marrow and in the mature erythrocytes leading to ineffective erythropoiesis and peripheral hemolysis. 1 IP:IPR000971 IP:IPR000971 activates MESH:D017086 Phenotype c48f3a56-7b87-11ee-ae93-0050569a1f61 10.1007/s00404-023-07032-6 The absence or decreased production of hemoglobin tetramer beta globin chains causes beta thalassemia (BT). 1 IP:IPR000971 IP:IPR000971 activates GO:0090579 Phenotype f038a164-bc19-11e5-9b9d-001a4ae51247 PMC2764439 BRG1 induces chromatin looping between the MRE and α2promotor and facilitates maximal RNA Polymerase II occupancy at the α2promotor BRG1 has been shown to mediate chromatin looping between far-upstream regulatory elements and promoters at theCIITAand β globin loci (12,43). 1 IP:IPR000971 IP:IPR000971 activates GO:0006955 Phenotype 615bd9b4-7851-11ee-9572-0050569a1f61 10.1007/s00580-023-03447-4 Bovera et al. (2015) reported lower albumin to globin ratio which induced immune response and better disease resistance in broiler chickens fed diets containing yellow mealworm. 1 IP:IPR000971 IP:IPR000971 activates GO:0010467 Phenotype 5c8fa64e-374e-11e8-bf76-001a4a160175 28774421 The haemopoietic system is convenient for such approaches, since haemopoietic stem cells from an individual with β-thalassaemia can be isolated and transduced with viruses to introduce exogenous genetic material, such as β-like globin transgenes that can allow for such exogenous gene expression. 1 IP:IPR000971 IP:IPR000971 activates GO:0010467 Phenotype d12a8580-8d82-11e7-a20e-001a4ae51247 28774657 The haemopoietic system is convenient for such approaches, since haemopoietic stem cells from an individual with β-thalassaemia can be isolated and transduced with viruses to introduce exogenous genetic material, such as β-like globin transgenes that can allow for such exogenous gene expression. 1 IP:IPR000971 IP:IPR000971 activates GO:0010467 Phenotype 6e6ec3c8-bc43-11e5-8d2d-001a4ae51247 PMC3280191 The finding that globin reduction significantly increased the sensitivity and significantly reduced the overall variance in gene expression profiles from both tubes was in line with previous studies reporting the positive impact of globin reduction on whole blood gene expression [6,9]. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0010467 Phenotype e3fb4708-bbd8-11e5-8abe-001a4ae51246 PMC3275489 Particularly, the presence of globin transcripts originating from reticulocytes in whole blood samples may limit the sensitivity of gene expression profiling experiments [14], since globin transcripts can constitute up to 70% of the total whole blood mRNA population [17]. 1 IP:IPR000971 IP:IPR000971 activates GO:0010467 Phenotype 9a905e84-bc12-11e5-8abe-001a4ae51246 PMC4673434 However, we chose to compare these two studies because whole blood samples from GSE53441 were submitted to a globin mRNA reduction step, which according to a well-designed study in sickle cell disease, minimizes differences and significantly increases the overlap of the gene expression profile compared to mononuclear cells16. 1 IP:IPR000971 IP:IPR000971 activates GO:0010467 Phenotype 82c9ee4c-c9a5-11ee-b346-0050569a791b PMC9840072 Debeyet al., showed that the presence of globin-mRNA complex leads to variability in analyzing gene expression by microarrays.58,59Large prospective studies with well-defined study designs are needed before the acceptance of biomarkers in clinical practice. 1 IP:IPR000971 IP:IPR000971 activates GO:0010467 Phenotype 532b82bc-374e-11e8-87fd-001a4a160176 28774463 The haemopoietic system is convenient for such approaches, since haemopoietic stem cells from an individual with β-thalassaemia can be isolated and transduced with viruses to introduce exogenous genetic material, such as β-like globin transgenes that can allow for such exogenous gene expression. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0010467 Phenotype 6e6ec3c8-bc43-11e5-8d2d-001a4ae51247 PMC3280191 In addition to different RNA collection methods, there is also a current debate whether high amounts of globin mRNA, originating from immature reticulocytes reduces the sensitivity to detect differently expressed genes and subsequently adversely impact gene expression profiling using microarrays [2]. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0006351 Phenotype b8843ea4-ca01-11e5-b88f-001a4ae51247 PMC1142595 In a β‐globin transcript lacking an intron or the ENE, decreased processing efficiency would increase the dwell time at the site of transcription and therefore provide a greater opportunity for export factors to bind in the absence of splicing. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0006351 Phenotype b441d198-dca5-11ea-8d75-001a4a160176 PMC6014909 Point mutations within the 5′UTR of the β globin gene reduced the rate of transcription resulting in thalassemia diseases, but did not interfere with mRNA transport from the nucleus to the cytoplasm, 3′ end processing, and mRNA stability [23]. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0006351 Phenotype ca2512dc-bbd8-11e5-9b9d-001a4ae51247 PMC3175478 In order to assess the need for globin reduction with the Illumina DASL assay, we compared microarray gene expression profiles of peripheral blood total RNA and globin-reduced RNA amplified via in vitro transcription (IVT)-based direct hybridization, DASL with globin-specific oligos, and DASL without globin-specific oligos. 1 IP:IPR000971 IP:IPR000971 activates GO:0006351 Phenotype 211b6d0e-ce6a-11e5-85cd-001a4ae51247 PMC358937 In this report, we have used recombinant adenovirus reporter vectors to characterize the mouse beta maj globin sequence elements that cause transcription termination. 1 IP:IPR000971 IP:IPR000971 activates GO:0006351 Phenotype f4dc7546-ca02-11e5-b88f-001a4ae51247 PMC1143763 "For example, globin locus control regions may enhance vector transcription from cryptic promoter sites in erythroid cells but not in lymphoid cells." 1 IP:IPR000971 IP:IPR000971 inhibits GO:0006351 Phenotype 9268a470-bc3d-11e5-ac4e-001a4ae51246 10.1016/S0022-2836(02)01011-2 A recent study has shown that hyperphosphorylated RNA pol II is localised to HS1, HS2 and HS3 in the mouse β globin LCR.39This localisation was not dependent on the presence of NF-E2, supporting our results, which show that mutation of the NF-E2 sites in the HS2 core region diminish but do not abolish transcription from within HS2. 1 IP:IPR000971 IP:IPR000971 activates GO:0006351 Phenotype defeddd2-bc19-11e5-9b9d-001a4ae51247 PMC2794187 It has been reported previously that a cluster of three GATA1 binding sites present in the α-globin gene domain downstream enhancer is sufficient for activation of transcription driven by globin gene promoters (23). 1 IP:IPR000971 IP:IPR000971 inhibits GO:0006351 Phenotype f2349c46-3c9a-11f0-afc2-0050569a791b 10.1016/j.bbagrm.2022.194850 This supports our hypothesis that the regulatory systems of globin gene domains in warm-blooded animals suppress bidirectional transcription. 1 IP:IPR000971 IP:IPR000971 activates GO:0006351 Phenotype b716e576-cb8c-11e5-8106-001a4ae51247 PMC305797 CCAAT consensus sequences are present in the minimal promoters of the human β‐like globin genes (deBoeret al., 1988;Liberatiet al., 1998) between a CACC box and a TATA box motif, all of which are necessary for efficient transcription (deBoeret al., 1988;Antoniouet al., 1995). 1 IP:IPR000971 IP:IPR000971 inhibits GO:0009058 Phenotype cd645424-c463-11e5-9cbe-001a4ae51247 PMC3552344 "As discussed briefly here, and in much more detail inThein (2013),Higgs (2013),Nienhuis and Nathan (2012), andMusallam et al. (2012), mutations of globin genes that impair synthesis give rise to thalassemia and anemia of varying degree." 1 IP:IPR000971 IP:IPR000971 activates GO:0009058 Phenotype 81817ffa-bbe9-11e5-9b9d-001a4ae51247 PMC3202272 The thalassemias are inherited disorders of α- or β-globin biosynthesis caused by mutations in the globin gene. 1 IP:IPR000971 IP:IPR000971 activates GO:0009058 Phenotype bb47a9e4-c472-11e5-9da3-001a4ae51247 PMC2754962 The final result of the α globin cluster rearrangements is the presence of one or two additional α globin genes, which cause a more severe imbalance of the α/β globin chain synthesis ratio, as compared to the simple β thalassemia carrier state. 1 IP:IPR000971 IP:IPR000971 activates GO:0009058 Phenotype 159385ee-bc4e-11e5-8d2d-001a4ae51247 PMC3962220 Hemoglobin consists of heme and globin, and when production of globin exceeds that of heme, HRI is activated and suppresses globin synthesis in erythrocytes by phosphorylating eIF2α. 1 IP:IPR000971 IP:IPR000971 activates GO:0009058 Phenotype 4f1a4830-bc3e-11e5-ac4e-001a4ae51246 PMC2893117 Most of these patients have excess functional alpha globin genes (alpha gene triplication or quadruplication) which increases the imbalance in the ratio of alpha/non-alpha globin chain synthesis [18,28]. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0009058 Phenotype 2580b03c-7f70-11ea-bf15-001a4a160176 PMC2873475 Five hundred nanograms of the globin-reduced RNA were then used for cRNA synthesis using the MessageAmp kit according to the manual supplied by the manufacturer (Ambion, Austin, TX). 1 IP:IPR000971 IP:IPR000971 activates GO:0009058 Phenotype f87f618f-f58d-11eb-9588-001a4a160176 31240559 Introduction introduction Thalassemia is a hereditary chronic hemolytic anemia that results from mutations of globin genes causing an imbalanced globin synthesis and ineffective erythropoiesis [1]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D006859 Phenotype 1d130582-bc4f-11e5-9b9d-001a4ae51247 10.1016/j.meatsci.2013.05.004 The electrostriction will affect dipolar water molecules leading to the disruption of ion pairs in the denatured globin (amino acid side chains) promoting the formation of intermolecular hydrogen bonds with water and positioning water molecules around the polypeptide, close to the nitrosylheme. 1 IP:IPR000971 IP:IPR000971 activates GO:0006935 Phenotype 77a1daca-c486-11e5-91a7-001a4ae51247 PMC3436268 HNgb is the first reported sensor that consists of a single globin domain alone, although some globin-coupled sensors in which globin domains are fused to methyl-accepting chemotaxis protein domains or domains for second-messenger regulation have been reported (55). 1 IP:IPR000971 IP:IPR000971 activates GO:0042311 Phenotype 3de4f680-f53e-11eb-ada5-001a4a160175 29355738 Globin proteins with coordinated iron atoms, such as hemoglobin, myoglobin, and neuroglobin, have been shown to trigger hypoxic vasodilation through the generation of NO and induce large downstream signaling[12]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D009355 Phenotype 471c2a5c-c479-11e5-8491-001a4ae51247 PMC3261562 The human tDNA‐containing fragments were cloned between the murine HS2 enhancer of the globin locus and a neomycin reporter driven by the human γ‐globin promoter. 1 IP:IPR000971 IP:IPR000971 activates MESH:D003681 Phenotype 4b986944-c928-11ee-b346-0050569a791b PMC9947981 Hemoglobin C mutation is a different amino acid substitution of the beta globin chain which promotes dehydration of the red blood cell [7]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D013789 Phenotype efd77aec-cbfa-11e5-b0dd-001a4ae51247 PMC109248 "Much of the globin mRNA in nonerythroid cells can be attributed to the high reticulocyte counts (∼15%) associated with a mild thalassemia caused by the excess of β-like globin chains in these and all other transgenic mouse lines described in this study (18)." 1 IP:IPR000971 IP:IPR000971 activates MESH:D013789 Phenotype 1a22f9f8-351b-11e8-9192-001a4a160175 PMC7162182 These systems use a mutation in human β‐globin that creates a new splice site and causes thalassemia. 1 IP:IPR000971 IP:IPR000971 activates MESH:D013789 Phenotype b2dcd796-c465-11e5-a92e-001a4ae51246 PMC3685880 Thalassemia is caused by mutations in the globin genes that lead to decreased production of hemoglobin. 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D013789 Phenotype 0d21f34a-bc09-11e5-9b9d-001a4ae51247 10.1016/j.clinbiochem.2013.09.013 Thalassemia is mainly caused by the gene fragment deletion of the globin gene or single point mutations. 1 IP:IPR000971 IP:IPR000971 activates MESH:D013789 Phenotype 19ef842e-bc41-11e5-8d2d-001a4ae51247 PMC4094851 These abnormal globin genes in different combinations lead to more than 60 thalassemia syndromes including three severe thalassemic diseases found in Thailand such as Hb Bart's hydrops fetalis (homozygousα-thalassemia 1, –/–), homozygousβ-thalassemia (β+/β+,β+/β0, orβ0/β0), andβ-thalassemia/Hb E (β+/βEorβ0/βE). 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D013789 Phenotype 46cad606-bc1e-11e5-9b9d-001a4ae51247 10.1016/j.jchromb.2010.04.017 Reduced synthesis of one of the globin chains can cause the formation of abnormal hemoglobin molecules, thus causing anemia, the characteristic presenting symptom of the thalassemia. 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D013789 Phenotype 2dd5dfd6-873d-11ee-add2-0050569a791b 10.1007/s00277-022-04915-7 While SCD is a structural disorder characterized by the production of abnormal hemoglobin called hemoglobin S (HbS) [1], thalassemias are caused by a quantitative deficiency of structurally normal globin chains [2]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D013789 Phenotype bb47a9e4-c472-11e5-9da3-001a4ae51247 PMC2754962 Recently Harteveldet al.16described segmental duplications of the α globin gene cluster causing thalassemia intermedia in 2 subjects hetorozygotes for β thalassemia. 1 IP:IPR000971 IP:IPR000971 activates MESH:D013789 Phenotype 10217512-bbf9-11e5-9b9d-001a4ae51247 10.1016/j.bcmd.2010.10.001 Introduction Hemoglobinopathies and thalassemia are caused by various mutations in the globin gene complex. 1 IP:IPR000971 IP:IPR000971 activates MESH:D013789 Phenotype 37a8c97e-5c15-11e7-8b40-001a4ae51247 PMC5437604 Thalassemia syndromes are caused by an absence or ineffective synthesis of beta globin chains. 1 IP:IPR000971 IP:IPR000971 activates MESH:D013789 Phenotype 0b539996-34f2-11e9-9cf0-001a4a160175 PMC6236037 Introduction intro Thalassemia beta was caused by a genetic disorder in globin β chain production. 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D013789 Phenotype c3bd3cc4-3405-11e8-bf76-001a4a160175 28284507 With an autosomal recessive inheritance, thalassemia is caused by deficiency or absence of beta globin chains. 1 IP:IPR000971 IP:IPR000971 activates MESH:D013789 Phenotype 966887cc-3ab0-11e8-8636-001a4a160175 24857170 The α globin gene triplication was previously described to cause intermediate thalassemia phenotypes when associated with a classical β-thalassemia mutation[12]. 1 IP:IPR000971 IP:IPR000971 activates GO:0019418 Phenotype 02c3e9e0-3406-11e8-9fbf-001a4a160176 PMC5392699 Reactivity of Fe We have postulated the presence of ferrous iron-bound hydrodisulfide (FeII-S-S−) as an intermediate in the globin-catalyzed sulfide oxidation reaction coordinate (11,12). 1 IP:IPR000971 IP:IPR000971 activates GO:0008283 Phenotype 050ae7c6-bbf9-11e5-9b9d-001a4ae51247 10.1016/j.bcmd.2009.01.015 Moreover, VPA has been shown to increase gamma globin gene expression[5–9,11]and stimulate erythroid proliferation[4,10]; however, no HbF or reticulocytes measurements were obtained in this study to confirm or disprove such an underlying mechanism or to explain its preferential occurrence at lower baseline Hb levels. 1 IP:IPR000971 IP:IPR000971 activates GO:0008283 Phenotype 3b677a10-352c-11e8-8636-001a4a160175 27599933 Further study is required to determine whether alpha globin induced by virus infection supports or inhibits the virus proliferation. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0008283 Phenotype ddd99b7a-c8eb-11e5-a4c6-001a4ae51246 PMC2573226 Sox6 promotes chondrogenesis (73), represses embryonic β-like globin transcription in definitive erythroid cells (91), and functions cell autonomously to promote proliferation, survival, and differentiation of erythroid cells (18). 1 IP:IPR000971 IP:IPR000971 activates GO:0006412 Phenotype 85c0ea7a-c480-11e5-a92e-001a4ae51246 PMC2975927 "To test first whether Rec8 protein translated from mRNA is loaded onto chromosomes, wild-type GV oocytes were injected with Rec8-Myc mRNA carrying 5′ and 3′ globin untranslated regions (UTRs), which are known to promote translation of H2B-mCherry mRNA in oocytes (McGuinness et al. 2009), and cultured in the presence of IBMX for 24 h before fixation." 1 IP:IPR000971 IP:IPR000971 activates GO:0006412 Phenotype 3611db2a-c8e9-11e5-9624-001a4ae51246 PMC2441975 "Addition of increasing concentrations of recombinant Gag did not seriously affect translation driven by the globin 5′-UTR (Fig. 7)." 1 IP:IPR000971 IP:IPR000971 inhibits GO:0006412 Phenotype 03c49450-c8e9-11e5-a1fd-001a4ae51246 18258918 Heme also initiates globin transcription through inhibiting the DNA binding of the repressor, Bach1 (1), and globin translation through inhibiting substrate phosphorylation by the repressor, erythroid-specific eukaryotic initiation factor 2α kinase (2). 1 IP:IPR000971 IP:IPR000971 inhibits GO:0006412 Phenotype 0368f4ce-0e67-11f0-b759-0050569a791b 10.1182/blood.V91.3.798 This question is particularly intriguing because globin mRNA translation is known to be regulated by the phosphorylation of the α-subunit of eukaryotic translation initiation factor (eIF-2α) by the heme-regulated eIF-2α kinase (HRI).8It is possible therefore that deficient heme synthesis may activate HRI and thus inhibit protein synthesis in ALAS-E–deficient erythroid cells. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0006412 Phenotype 07da9a8c-d1ac-11e5-85cd-001a4ae51247 PMC396988 After injection into frog oocyte cytoplasm, the anti-sense globin RNA forms a hybrid with globin mRNA and selectively prevents its translation. 1 IP:IPR000971 IP:IPR000971 activates GO:0006412 Phenotype 14952986-c482-11e5-91a7-001a4ae51247 PMC3442272 To verify this, we have added hippuristanol to DDX3‐depleted cells and looked at translation driven by the globin or the HIV‐1 5′‐UTR. 1 IP:IPR000971 IP:IPR000971 activates GO:0006412 Phenotype 454af7d8-bc51-11e5-ac4e-001a4ae51246 10.1016/j.virusres.2009.08.008 In this study, these ODNs were screened for their inhibitory effects on HCV IRES-mediated translation with chimeric HCV-polioviral genome [P/H(1a)] and rabbit globin mRNA. 1 IP:IPR000971 IP:IPR000971 activates GO:0032774 Phenotype d040b85e-bc43-11e5-9b9d-001a4ae51247 PMC31331 Previous studies by Volloch and coworkers have reported that during the expression of high levels of β-globin mRNA in the spleen of anemic mice, they could also detect small but significant levels of an antisense (AS) globin RNA species, which they postulated might have somehow arisen by RNA-directed RNA synthesis. 1 IP:IPR000971 IP:IPR000971 activates MESH:D009569 Phenotype 4d325eae-bc02-11e5-9b9d-001a4ae51247 10.1016/j.niox.2013.06.002 The globin Cgb, but not the truncated globin Ctb, restores GSNO and NO resistance to a flavohaemoglobin mutant ofE. 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D009569 Phenotype 768c9fda-c982-11ee-b346-0050569a791b 10.1016/j.freeradbiomed.2022.11.035 The globin family proteins, such as neuroglobin (Ngb), hemoglobin and cytoglobin, may also inactivate NO in the brain [156,157]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D009569 Phenotype 63dafc38-354e-11e9-8325-001a4a160175 29275194 Since the transcription of FHb-encoding genes is linked to globin-mediated NO detoxification [46,50,61], the observed FHb-gene expression is suggestive of the occurrence of NO-induced stress intimately correlated to the absence ofPh-2/2HbO-0030. 1 IP:IPR000971 IP:IPR000971 activates MESH:D009569 Phenotype dafb6070-c8e9-11e5-9ad8-001a4ae51247 PMC2661400 Likely roles for iron proteins are in respiration, a key target of nitrosative damage (Figs.1and S1), and in globin-mediated NO detoxification. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0001171 Phenotype 1724e4e0-c8e0-11e5-a1fd-001a4ae51246 PMC1876175 The method from Affymetrix uses the specific binding of peptide nucleic acid (PNA) oligos to the 3′ end of globin mRNA to inhibit reverse transcription during cDNA synthesis.2The method from Ambion, removes globin mRNA from total RNA via hybridization with biotinylated DNA oligos that specifically capture globin mRNA followed by binding with streptavidin magnetic beads. 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D012965 Phenotype 7081aaca-c8e8-11e5-9cb8-001a4ae51247 17928589 Translation of globin mRNA by rabbit reticulocyte lysate in vitro is inhibited when osmolality is increased by adding NaCl, KCl, CH3CO2Na, or CH3CO2K, but not by adding the compatible osmolytes betaine ormyo-inositol (26). 1 IP:IPR000971 IP:IPR000971 activates MESH:D010100 Phenotype bd32888c-de52-11e6-88e7-001a4ae51246 PMC5337469 These Hb variants, in which the alteration of the globin structure due to a genetic mutation causes the low oxygen affinity of Hb, are very rare. 1 IP:IPR000971 IP:IPR000971 activates MESH:D010100 Phenotype 07c597b6-bc32-11e5-8abe-001a4ae51246 PMC3699623 This adaptation has been attributed to changes in the primary structure of globin chains, which modulates oxygen uptake and delivery to the tissues. 1 IP:IPR000971 IP:IPR000971 activates MESH:D010100 Phenotype bc21a3c2-bbff-11e5-9b9d-001a4ae51247 10.1016/j.bbrc.2004.10.209 This adaptation has been attributed to changes in the primary structure of globin chains, which modulates oxygen uptake and delivery to the tissues. 1 IP:IPR000971 IP:IPR000971 activates MESH:D010100 Phenotype e8ac80a2-de09-11e5-9301-001a4ae51247 PMC4824146 For example, an important adaptation of subterranean mole rats to environmental hypoxia is mediated by higher tissue globin expression (e.g., NGB) (compared with rat), high blood–oxygen affinity, and high Hct (Van Aardt et al. 2007;Avivi et al. 2010). 1 IP:IPR000971 IP:IPR000971 inhibits GO:0006402 Phenotype 25f5888a-8dc4-11e7-955b-001a4ae51246 PMC5340968 "Moreover, rabbit beta globin reporter analysis supported the idea that p-UPF1 binding motifs are responsible for UPF1-mediated mRNA degradation (Figs." 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D016393 Phenotype f27ed168-027e-11e6-92aa-001a4ae51246 PMC4811061 Thrombin Upregulates the Expression of Globin Transcription Factor 1 and Downregulates the Expression of B-Cell Lymphoma 2 To examine the expression of globin transcription factor 1 (GATA-1) and B-cell lymphoma 2 (Bcl-2), quantitative real-time polymerase chain reaction (PCR) was used. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0006783 Phenotype 39e9e398-5ca7-11e7-af4d-001a4ae51247 PMC5290819 In erythroid cells synthesizing vast amounts of hemoglobin, Bach1 is limiting, which favors globin gene expression and contributes to a balance between globin chain and heme biosynthesis [6]. 1 IP:IPR000971 IP:IPR000971 activates GO:0006783 Phenotype 97edc150-c47b-11e5-9cc6-001a4ae51246 21636714 The accumulation of globin messenger RNA, increased iron assimilation and heme biosynthesis, accumulation of hemoglobin, the emergence of erythrocyte membrane proteins, cell-cycle arrest, and accumulation of hyperacetylated histone. 1 IP:IPR000971 IP:IPR000971 activates MESH:D007501 Phenotype d5c466b8-c47c-11e5-8491-001a4ae51247 PMC3130418 Beta-thalassemia, which results from defective synthesis of beta globin leading to progressive anaemia requiring blood transfusions and iron chelation therapy, has been modelled by reprogramming patient fibroblasts, amniotic fluid cells or chorionic villus sample cells [17]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D006461 Phenotype 0e6de886-352d-11e8-87fd-001a4a160176 27049126 Distribution After absorption, arsenic rapidly binds with globin portion of hemoglobin which causes hemolysis and therefore transported through blood to other parts of the body. 1 IP:IPR000971 IP:IPR000971 activates MESH:D006461 Phenotype 8efdd59a-dc96-11ea-8c8a-001a4a160176 PMC6168382 Unbound α globin aggregates on erythrocyte membrane to form Heinz bodies and eventually causes hemolysis due to membrane destruction and overexposure to oxidative stress[48,49]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D006461 Phenotype 5bcdff2a-bc0e-11e5-8abe-001a4ae51246 10.1016/j.micron.2011.10.018 The unbalanced globin chain synthesis that occurs in thalassemia may lead to the formation of either free α-chains or β-chains, which precipitate into the cytoplasm of erythroid precursors and lead to the premature death of these cells and the hemolysis of mature red blood cells (Testa, 2004; Schrier, 2002). 1 IP:IPR000971 IP:IPR000971 activates MESH:D006461 Phenotype 292e4b58-c468-11e5-91a7-001a4ae51247 PMC3648058 "Hence, it is proposed that delayed translation of globin mRNA results in a relative increase in free heme, causing oxidative stress and hemolysis of erythroid progenitors and producing the anemic phenotype in DBA (12,26)." 1 IP:IPR000971 IP:IPR000971 activates MESH:D013936 Phenotype c2079104-3aa4-11e8-bf76-001a4a160175 25931326 Discussion Hb M Iwate arises due to a point mutation in either α1 or α2 globin chains causing substitution of a thymidine (T) instead of cytosine (C) in codon 262 i.e. HBA1 (or HBA2): codon 262C>T and a resultant substitution of tyrosine instead of histidine in position 87 of the α-globin protein[4,6,7]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D008708 Phenotype bde6e628-bbd6-11e5-9b9d-001a4ae51247 PMC3036099 In this report, we describe a novel mutation in the α globin gene, which caused non-debilitating congenital methemoglobinemia in a family, with cyanosis as the only obvious manifestation.The family came from Yantai, Shan-Dong Province, China. 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D006965 Phenotype 771e4186-bc22-11e5-9b9d-001a4ae51247 PMC101377 In these affections the persistent synthesis of Hb F is very important because it restores the alpha/non-alpha globin ratio, thus reducing the bone marrow hyperplasia and ineffective erythropoiesis and therefore the severity of disease. 1 IP:IPR000971 IP:IPR000971 activates MESH:D060467 Phenotype 615bd9b4-7851-11ee-9572-0050569a1f61 10.1007/s00580-023-03447-4 Bovera et al. (2015) reported lower albumin to globin ratio which induced immune response and better disease resistance in broiler chickens fed diets containing yellow mealworm. 1 IP:IPR000971 IP:IPR000971 activates MESH:D019636 Phenotype 3009809a-c8ec-11e5-878b-001a4ae51247 PMC2652363 Examples include neurodegenerative disorders, cataracts, the major form of cystic fibrosis, and myopathies.19-22In the thalassemia syndromes, synthetic imbalance of globin chains leads to the formation of toxic protein precipitates in erythroid cells.23,24In this way, the thalassemias are largely disorders of unstable protein accumulation and, therefore, potentially subject to modulation by protein quality control pathways.In addition to interacting with denatured proteins, molecular chaperones bind many native folded proteins to modulate their cellular activities. 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D016914 Phenotype b226ec6e-bbd8-11e5-8abe-001a4ae51246 PMC4446061 The globin transcripts (HBAandHBB) were reduced using an RNase H based globin reduction method [23] that used porcine specific oligonucleotides modified from an Affymetrix GeneChip GR Protocol for reduction of human globin mRNA. 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D016914 Phenotype 66511bea-5c20-11e7-af4d-001a4ae51247 PMC5385538 The globin transcripts (HBA and HBB) were reduced using an RNase H based globin reduction method33and RNA quality was assessed again. 1 IP:IPR000971 IP:IPR000971 activates MESH:D010455 Phenotype 2a41115c-ae94-11ec-8f68-0050569a1f61 PMCPMC8865197 NMD prevented mature β‐globin production yet produced the antigenic peptide via pioneer round of translation. 1 IP:IPR000971 IP:IPR000971 activates GO:0030154 Phenotype 2caaabb0-ae94-11ec-ae7b-0050569a1f61 PMCPMC8548687 Therefore, the K562 cell appears to be an excellent tool for the study of human erythroid differentiation and globin gene expression.We induced K562 erythroid differentiation by treated with hemin, to find TPR functions in erythroid differentiation. 1 IP:IPR000971 IP:IPR000971 activates GO:0030154 Phenotype 62681520-3757-11e8-87fd-001a4a160176 27283485 Histone deacetylase inhibitors (HDACIs) such as butyric acid (BA) activate expression of the globin genes, and induce differentiation of erythroid cells (Ikuta et al., 1998; Canh Hiep et al., 2012; Steliou et al., 2012). 1 IP:IPR000971 IP:IPR000971 activates GO:0030154 Phenotype 1f1865c8-bc24-11e5-8abe-001a4ae51246 10.1016/j.beha.2013.09.007 Epo induces globin gene expression and specifically promotes late erythroid differentiation, cooperating with GATA-1, a transcription factor that plays crucial role in erythroid development[19]. 1 IP:IPR000971 IP:IPR000971 activates GO:0030154 Phenotype 32add0f2-c465-11e5-a92e-001a4ae51246 PMC3811682 "Since miR-23a and miR-27a are demonstrated to promote erythroid differentiation, there should be other mechanisms and targets of miR-23a and miR-27a in the regulation of erythroid differentiation or α-like globin gene expression." 1 IP:IPR000971 IP:IPR000971 inhibits GO:0030154 Phenotype 62681520-3757-11e8-87fd-001a4a160176 27283485 Histone deacetylase inhibitors (HDACIs) such as butyric acid (BA) activate expression of the globin genes, and induce differentiation of erythroid cells (Ikuta et al., 1998; Canh Hiep et al., 2012; Steliou et al., 2012). 1 IP:IPR000971 IP:IPR000971 activates GO:0030154 Phenotype 0fcbf890-bc52-11e5-9b9d-001a4ae51247 10.1016/j.leukres.2010.07.033 Epo induces globin gene expression and specifically promotes late erythroid differentiation, cooperating with GATA-1, a transcription factor that plays a critical role in erythroid development. 1 IP:IPR000971 IP:IPR000971 activates GO:0030154 Phenotype 14c5a4de-bc27-11e5-9b9d-001a4ae51247 10.1016/j.mehy.2009.11.033 The resulting haemoglobin accumulation into the cell would inhibit further synthesis of both globin and heme and cell proliferation, which would ultimately cause the irreversible and complete differentiation of mature red cell. 1 IP:IPR000971 IP:IPR000971 activates GO:0030154 Phenotype aabf7a8e-bc39-11e5-8abe-001a4ae51246 PMC2964535 Globin mRNA levels in the lentivirus-infected CD34+ cells were analyzed by real-time PCR before and after Epo-induced erythroid differentiation. 1 IP:IPR000971 IP:IPR000971 activates MESH:D051379 Phenotype d3ecc122-8dad-11e7-a20e-001a4ae51247 PMC5374354 Because β-globin levels are reduced and embryonic globin levels are increased inKlf1−/−mice (Bieker, 2010), it has been postulated that the induction of human γ-globin levels by knockdown ofKLF1could serve as a viable therapeutic strategy for individuals with sickle-cell anemia or β-thalassemia (Bieker, 2010). 1 IP:IPR000971 IP:IPR000971 activates MESH:D051379 Phenotype 16b830d2-c473-11e5-91a7-001a4ae51247 PMC2738712 This might have resulted from the inversed imbalance of globin synthesis in these mice (Figure 1). 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D051379 Phenotype 1f78a27a-c8e6-11e5-9cb8-001a4ae51247 PMC2200909 This had previously been reported forKLF2−/−embryos.9The mouse embryonic β-like globin genes are down-regulated inEKLFnull mice. 1 IP:IPR000971 IP:IPR000971 phosphorylatesProtein MESH:D051379 Phenotype 9ce474c2-c8dd-11e5-a1fd-001a4ae51246 PMC1430266 "This is consistent with the opposing effects of HRI kinase and Gadd34/PP1c on eIF2α(S51) phosphorylation and globin synthesis in reticulocytes.Gadd34-null mice have reduced hemoglobin content (Table1), whileHRI-null mice have increased hemoglobin content (9)." 1 IP:IPR000971 IP:IPR000971 activates GO:0006915 Phenotype 845f6124-c481-11e5-a92e-001a4ae51246 PMC3331689 "Studies with HRI-deficient mice showed that HRI protects erythroid precursors from apoptosis induced by excessive production of globin chains and contributes to the microcytosis and hypochromia seen in iron deficiency, erythropoietic protoporphyria, and β-thalassemia." 1 IP:IPR000971 IP:IPR000971 activates GO:0006915 Phenotype c50b047a-c478-11e5-91a7-001a4ae51247 21558467 "The anemia is caused by excess, unbalanced alpha globin chains that are toxic to the red blood cell, leading to apoptosis of developing erythroblasts at the polychromatophilic normoblast stage with intramedullary hemolysis (Rund and Rachmilewitz 2005;Perrine 2005;Schrier 1997;Koury, Sawyer, and Brandt 2002;Centis et al. 2000;Testa 2004;Mathias et al. 2000;Yuan et al. 1993;Pootrakul et al. 2000;Silva et al. 1996)." 1 IP:IPR000971 IP:IPR000971 activates GO:0006915 Phenotype 4ef5af4e-2ab2-11e9-aa64-001a4a160176 PMC6334984 Heme-free globin reportedly causes apoptosis in cultured cells [50,51]. 1 IP:IPR000971 IP:IPR000971 activates GO:0008219 Phenotype 80cb9c3a-c472-11e5-a92e-001a4ae51246 PMC2680376 In humans, free α globin chains in differentiating thalassemic erythroblasts can cause premature cell death by apoptosis.1–3Apoptosis of early and late erythroblasts was analyzed by flow cytometry after binding to fluorescent-labeled annexin V (Figure 3B andTable 3).32There was a significant increase in annexin V+early and late erythroblasts (regions II and III) in the bone marrow of CA mice. 1 IP:IPR000971 IP:IPR000971 activates MESH:D000860 Phenotype f9107f8e-3796-11e6-8a17-001a4ae51247 PMC4998755 Firstly, insufficient globin causes anemia and hypoxia. 1 IP:IPR000971 IP:IPR000971 activates MESH:D000860 Phenotype 98180e0c-bbd8-11e5-956b-001a4ae51247 PMC1435884 If death occurs during the second third of the yolk sac stage (intermediate group), the terminal stage is preceded by a clear disturbance in globin gene expression, which will lead to internal hypoxia, when the animals grow and shift from predominantly skin-breathing to gill-breathing. 1 IP:IPR000971 IP:IPR000971 activates MESH:D003643 Phenotype 5bcdff2a-bc0e-11e5-8abe-001a4ae51246 10.1016/j.micron.2011.10.018 The unbalanced globin chain synthesis that occurs in thalassemia may lead to the formation of either free α-chains or β-chains, which precipitate into the cytoplasm of erythroid precursors and lead to the premature death of these cells and the hemolysis of mature red blood cells (Testa, 2004; Schrier, 2002). 1 IP:IPR000971 IP:IPR000971 activates GO:0006954 Phenotype d68687b8-c8e9-11e5-9ad8-001a4ae51247 PMC2604845 To determine whether globin and Cx43 dsRNA could induce an inflammatory response, we evaluated their potential capacity to activate the nuclear factor-kappa B (NF-κB). 1 IP:IPR000971 IP:IPR000971 activates MESH:D013577 Phenotype edfc9f1c-c8e5-11e5-9624-001a4ae51246 17715390 Globin gene expression plays a central role in normal erythropoiesis, and abnormalities of globin synthesis underlie the clinically important thalassaemia syndromes. 1 IP:IPR000971 IP:IPR000971 activates MESH:D013577 Phenotype 37a8c97e-5c15-11e7-8b40-001a4ae51247 PMC5437604 Thalassemia syndromes are caused by an absence or ineffective synthesis of beta globin chains. 1 IP:IPR000971 IP:IPR000971 activates MESH:D013577 Phenotype 40a6c17c-4bf9-11e9-b191-001a4a160176 PMC6426207 β-thalassemia is an example of this syndrome, caused by a defective quality and quantity of the beta globin chain production resulting in a decreased quantity of beta globin chains. 1 IP:IPR000971 IP:IPR000971 activates MESH:D013577 Phenotype 3009809a-c8ec-11e5-878b-001a4ae51247 PMC2652363 Examples include neurodegenerative disorders, cataracts, the major form of cystic fibrosis, and myopathies.19-22In the thalassemia syndromes, synthetic imbalance of globin chains leads to the formation of toxic protein precipitates in erythroid cells.23,24In this way, the thalassemias are largely disorders of unstable protein accumulation and, therefore, potentially subject to modulation by protein quality control pathways.In addition to interacting with denatured proteins, molecular chaperones bind many native folded proteins to modulate their cellular activities. 1 IP:IPR000971 IP:IPR000971 activates MESH:D001710 Phenotype 9502fd4e-bc05-11e5-9b9d-001a4ae51247 PMC4228284 The inhibition of globin cDNA synthesis dramatically reduces the relative amount of anti-sense, biotin-labeled cRNA corresponding to the hemoglobin transcripts (http://www.expressionanalysis.com/images/uploads/tech_notes/Globin_Tech_Note_final_v2.pdf). 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D001710 Phenotype 9e5056ae-5c2b-11e7-9833-001a4ae51246 PMC5335253 Globin mRNA was subsequently depleted using the GLOBINclear Kit (Ambion), amplified and biotin-labelled using the TotalPrep RNA Amplification Kit (Illumina). 1 IP:IPR000971 IP:IPR000971 activates MESH:D006427 Phenotype b248d290-c469-11e5-9da3-001a4ae51247 PMC3811770 Autooxidation of globin-bound Fe2+-protoporphyrin (heme) produces the ferric (Fe3+) form (hemin) with concomitant production of superoxide (O2−), generating methemoglobin and metmyoglobin. 1 IP:IPR000971 IP:IPR000971 activates GO:1903409 Phenotype de6f1a11-f598-11eb-9863-001a4a160176 31190133 The excess alpha globin induces ROS generation and promotes RBC destruction. 1 IP:IPR000971 IP:IPR000971 activates GO:0034440 Phenotype 1a8d1096-bc4f-11e5-ac4e-001a4ae51246 10.1016/j.meatsci.2013.04.053 Above 400MPa the globin part is denatured, probably leading to the release of the iron and increased lipid oxidation (Carlez, Veciana-Nogues, & Cheftel, 1995). 1 IP:IPR000971 IP:IPR000971 activates GO:0034440 Phenotype d8e2ec6c-3756-11e8-b868-001a4a160176 25148987 These results are consistent with haemin released from the globin causing lipid oxidation and porphyrin degradation when considering both trout and bovine Hb; just that the onset of lipid oxidation was more rapid with the fish Hb due to its more rapid rate of haemin dissociation while the extents of lipid oxidation due to trout and bovine metHb were similar. 1 IP:IPR000971 IP:IPR000971 activates GO:0043934 Phenotype 7a0e17ec-c481-11e5-a92e-001a4ae51246 PMC3416556 Characterization of two similar nonheme globin domains that modulate sporulation inBacillus anthracissuggests that they are capable of sensing fatty acids and chloride via binding within a distinctive tunnel and chamber (41). 1 IP:IPR000971 IP:IPR000971 activates MESH:D001663 Phenotype 940c12cc-ae93-11ec-89b1-0050569a791b PMCPMC8269253 Compared to those observed in HCs, the erythrocyte sedimentation rate (ESR), C-reactive proteins (CRP), granulocytes, neutrophils, platelet distribution width, total protein, globin, alkaline phosphatase, and γ-glutamyltransferase were increased, whereas the lymphocytes, eosinophils, mean erythrocyte hemoglobin concentration, mean platelet volume, direct bilirubin, indirect bilirubin, and creatinine levels were decreased in AS patients. 1 IP:IPR000971 IP:IPR000971 activates GO:0042540 Phenotype df3a42d0-352c-11e8-bf76-001a4a160175 27032973 A cSDH is characterized by repeat episodes of rebleeding along vascularized neomembranes, thus containing varying amounts of albumin, hemoglobin, and hemoglobin breakdown products, including hemosiderin and globin proteins.6,7The various proteins increase T1 and FLAIR signal, and paramagnetic/ferromagnetic hemosiderin causes blooming on T2*-GRE/SWI. 1 IP:IPR000971 IP:IPR000971 activates GO:0042541 Phenotype adbee5ca-bbf4-11e5-8abe-001a4ae51246 10.1016/S0301-472X(01)00669-5 Hemoglobin synthesis directed by stable globin transcripts continues until cell replication ceases[17,18]. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0042541 Phenotype 8aae033a-390c-11e8-bf76-001a4a160175 27263053 Introduction Thalassemia is a quantitative deficiency of functional α- and β-like globin chains synthesis that leads to ineffective erythropoiesis and reduced hemoglobin synthesis. 1 IP:IPR000971 IP:IPR000971 activates GO:0042168 Phenotype 399dfd5a-bc32-11e5-9b9d-001a4ae51247 PMC3704632 Our model for knockdown of beta-globin gene expression may also permit examinations of dysfunctional erythroblast heme metabolism or mitochondrial function caused by globin chain imbalance[32]. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0006479 Phenotype 44bf91aa-bc3a-11e5-8d2d-001a4ae51247 PMC3599103 Because Adox can inhibit both DNA methylation and protein methylation including histone tail methylation, we performed bisulfite DNA sequencing experiments on globin genes. 1 IP:IPR000971 IP:IPR000971 activates MESH:D006453 Phenotype ecee1e30-56c2-11e8-8d4f-001a4a160176 PMC5976019 Thalassemia is a hemoglobinopathy caused by the alterations of globin chain synthesis that is classified into 2 forms based on the abnormality of globin chains,i.e., α and β-thalassemia. 1 IP:IPR000971 IP:IPR000971 activates MESH:D006453 Phenotype a98ab0be-bc09-11e5-8abe-001a4ae51246 PMC3033156 Similarly to SCD, other hemoglobinopathies can be triggered by the substitution of one amino acid (HbE5,6,2), deletion of a portion of the amino acid sequence (Hb Gun Hill7), abnormal hybridization between two chains (Hb Lepore8,9), or abnormal elongation of the globin chain (Hb Constant Spring10). 1 IP:IPR000971 IP:IPR000971 activates MESH:D006453 Phenotype 234619d2-c46d-11e5-85e4-001a4ae51246 PMC4484743 Hemoglobinopathies The hemoglobinopathies are a group of inherited blood disorders caused by mutations in the globin genes and includes SCD and the thalassemias. 1 IP:IPR000971 IP:IPR000971 activates MESH:D006453 Phenotype e6df6f72-390c-11e8-8f56-001a4a160175 PMC5001899 Mutations in adult globin genes cause hemoglobinopathies such as sickle cell disease (SCD) and thalassemia, which are among the most common monogenic inherited human disorders [136,137]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D006453 Phenotype 9135b780-c482-11e5-9cc6-001a4ae51246 23118216 To the editor: Sickle cell disease (SCD) is a hemoglobinopathy caused by a single amino acid change in the β globin subunit that predisposes hemoglobin to abnormal polymerization leading to stiff, sickled erythrocytes, and microvascular occlusions.1Although the vascular consequences of SCD are triggered by changes in the erythrocyte,2a chronic inflammatory state often ensues with many other cell types contributing to SCD pathology. 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D008288 Phenotype b6b2928a-bc44-11e5-ac4e-001a4ae51246 PMC3894252 Mutations in various human globin genes, the glucose-6-phosphate dehydrogenase gene, and the Duffy blood-group locus are known to reduce malaria susceptibility or to alter the clinical course of this disease (Abu-Zeid et al., 1992; Balgir, 2008; Sarkar et al., 2010; Williams et al., 2005). 1 IP:IPR000971 IP:IPR000971 activates GO:0006983 Phenotype 19ef842e-bc41-11e5-8d2d-001a4ae51247 PMC4094851 These abnormal globin genes in different combinations lead to more than 60 thalassemia syndromes including three severe thalassemic diseases found in Thailand such as Hb Bart's hydrops fetalis (homozygousα-thalassemia 1, –/–), homozygousβ-thalassemia (β+/β+,β+/β0, orβ0/β0), andβ-thalassemia/Hb E (β+/βEorβ0/βE). 1 IP:IPR000971 IP:IPR000971 activates MESH:D003490 Phenotype bde6e628-bbd6-11e5-9b9d-001a4ae51247 PMC3036099 In this report, we describe a novel mutation in the α globin gene, which caused non-debilitating congenital methemoglobinemia in a family, with cyanosis as the only obvious manifestation.The family came from Yantai, Shan-Dong Province, China. 1 IP:IPR000971 IP:IPR000971 activates GO:0033212 Phenotype 97edc150-c47b-11e5-9cc6-001a4ae51246 21636714 The accumulation of globin messenger RNA, increased iron assimilation and heme biosynthesis, accumulation of hemoglobin, the emergence of erythrocyte membrane proteins, cell-cycle arrest, and accumulation of hyperacetylated histone. 1 IP:IPR000971 IP:IPR000971 activates MESH:D013481 Phenotype 0eb998f4-bc25-11e5-9b9d-001a4ae51247 PMC4013584 The protein encoded by this gene is a member of the globin molecule family with a double functional nature: antioxidant activity, inducing superoxide dismutase, and anti-apoptotic activity, inhibiting the apoptotic effects of caspase-2 and caspase-3 [149–152]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D012333 Phenotype 9e0a9d4e-d6cb-11e5-81c0-001a4ae51246 PMC388182 Appropriate control experiments indicate that the virus-associated globin messenger RNA is resistant to degradation by exogenous ribonuclease; that exogenously added globin messenger RNA does not become associated with the 60S viral RNA complex; and that globin messenger RNA can be detected in virions derived from cells both induced for and constitutively synthesizing globin messenger RNA. 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D000740 Phenotype 3fe6f5fa-3911-11e8-8636-001a4a160175 20207263 Thalassemia defines a form of anemia caused by reduced synthesis of one of the normal globin chains, which results in an abnormal hemoglobin molecule. 1 IP:IPR000971 IP:IPR000971 activates MESH:D000740 Phenotype f9107f8e-3796-11e6-8a17-001a4ae51247 PMC4998755 Firstly, insufficient globin causes anemia and hypoxia. 1 IP:IPR000971 IP:IPR000971 activates MESH:D000740 Phenotype 45f9f908-5c42-11e7-9fde-001a4ae51247 PMC5154712 Background Heterozygous beta thalassemia minor (HBT) is a benign blood disorder caused by a hereditary reduction in beta globin synthesis, which often leads to mild anemia and is characterized by hypochromic microcytic erythrocyte indexes [1]. 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D000740 Phenotype c5a1e71a-ae95-11ec-a61d-0050569a1f61 PMCPMC8564650 Thalassemia is a type of hypochromic microcytic anemia caused by a lack of or decreased synthesis of hemoglobin's globin chain. 1 IP:IPR000971 IP:IPR000971 activates MESH:D000740 Phenotype 3186b0dc-c956-11ee-b346-0050569a791b 10.1016/j.jacc.2022.08.812 The reduced or absent beta globin chain synthesis results in an excess of alpha chains, causing severe anemia. 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D000740 Phenotype 0a8ccc48-ae94-11ec-ae7b-0050569a1f61 PMCPMC8589257 Inducing expression of fetal globin (γ-globin) gene expression to 60% to 70% of α-globin synthesis produces β-thalassemia trait globin synthetic ratios and has been shown to reduce anemia to mild levels that do not require regular blood transfusions. 1 IP:IPR000971 IP:IPR000971 activates MESH:D000740 Phenotype c50b047a-c478-11e5-91a7-001a4ae51247 21558467 "The anemia is caused by excess, unbalanced alpha globin chains that are toxic to the red blood cell, leading to apoptosis of developing erythroblasts at the polychromatophilic normoblast stage with intramedullary hemolysis (Rund and Rachmilewitz 2005;Perrine 2005;Schrier 1997;Koury, Sawyer, and Brandt 2002;Centis et al. 2000;Testa 2004;Mathias et al. 2000;Yuan et al. 1993;Pootrakul et al. 2000;Silva et al. 1996)." 1 IP:IPR000971 IP:IPR000971 inhibits MESH:D000740 Phenotype 46cad606-bc1e-11e5-9b9d-001a4ae51247 10.1016/j.jchromb.2010.04.017 Reduced synthesis of one of the globin chains can cause the formation of abnormal hemoglobin molecules, thus causing anemia, the characteristic presenting symptom of the thalassemia. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0030218 Phenotype 771e4186-bc22-11e5-9b9d-001a4ae51247 PMC101377 In these affections the persistent synthesis of Hb F is very important because it restores the alpha/non-alpha globin ratio, thus reducing the bone marrow hyperplasia and ineffective erythropoiesis and therefore the severity of disease. 1 IP:IPR000971 IP:IPR000971 activates GO:0030218 Phenotype 40a6c17c-4bf9-11e9-b191-001a4a160176 PMC6426207 The decrease in beta-globin chain production results in an excess of alpha globin chains; the more excessive alpha globin chains cause a more severe early apoptosis and ineffective erythropoiesis in the bone marrow. 1 IP:IPR000971 IP:IPR000971 activates GO:0030218 Phenotype 8aae033a-390c-11e8-bf76-001a4a160175 27263053 Introduction Thalassemia is a quantitative deficiency of functional α- and β-like globin chains synthesis that leads to ineffective erythropoiesis and reduced hemoglobin synthesis. 1 IP:IPR000971 IP:IPR000971 activates GO:0030218 Phenotype 5f1dd124-ae96-11ec-b4ed-0050569a1f61 PMCPMC8719792 Beta-thalassemia major (ß-TM), also known as Cooley' s anemia or Mediterranean anemia, is an inherited disorder of beta globin chain synthesis, which leads to ineffective erythropoiesis and requires chronic blood transfusion therapy (1). 1 IP:IPR000971 IP:IPR000971 inhibits GO:0006306 Phenotype 44bf91aa-bc3a-11e5-8d2d-001a4ae51247 PMC3599103 Because Adox can inhibit both DNA methylation and protein methylation including histone tail methylation, we performed bisulfite DNA sequencing experiments on globin genes. 1 IP:IPR000971 IP:IPR000971 activates GO:0000746 Phenotype dfa36c3e-bc47-11e5-8abe-001a4ae51246 10.1016/j.bbapap.2011.03.007 They found that ubiquitin conjugation to globin was markedly enhanced by denaturation of hemoglobin and the concentration of globin–ubiquitin conjugates was proportional to the rate of hemoglobin degradation[60]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D017085 Phenotype bb2ca6ac-bbd6-11e5-8abe-001a4ae51246 PMC4612597 Alpha thalassemia can be caused by the deletion of one or both alpha globin genes (α1and α2) (Harteveld and Higgs, 2010), and the most common cause of the condition in Brazil is the deletion of the −α3.7kbgene as a result of homologous recombination between misaligned chromosomes (Sonatiet al., 1991;Wagneret al., 2010). 1 IP:IPR000971 IP:IPR000971 activates MESH:D017085 Phenotype c37dff3a-c47e-11e5-91a7-001a4ae51247 PMC2840985 "The association of ATRX mutations with a reduction in alpha globin synthesis in alpha thalassemia patients suggests that the protein plays a role in the regulation of alpha globin gene expression." 1 IP:IPR000971 IP:IPR000971 activates MESH:D026422 Phenotype 4d325eae-bc02-11e5-9b9d-001a4ae51247 10.1016/j.niox.2013.06.002 The globin Cgb, but not the truncated globin Ctb, restores GSNO and NO resistance to a flavohaemoglobin mutant ofE. 1 IP:IPR000971 IP:IPR000971 activates MESH:D004915 Phenotype b4ed6738-c485-11e5-85e4-001a4ae51246 PMC3504731 DISCUSSION This study reveals for the first time, to our knowledge, a crucial role for ADNP and ADNP2, each separately, in globin synthesis and erythropoiesis in two model systems, the zebrafish and the murine erythroleukemia cell. 1 IP:IPR000971 IP:IPR000971 activates MESH:D004915 Phenotype 074d5488-bbf9-11e5-8abe-001a4ae51246 10.1016/j.bcmd.2007.05.003 Our data indicate that globin regulatory elements significantly increase promoter trapping efficiency in human erythroleukemia cells but not in HeLa cells, consistent with the functional, erythroid specificity of the globin regulatory elements[14]. 1 IP:IPR000971 IP:IPR000971 activates MESH:D004915 Phenotype 807999b6-d2ce-11e5-888a-001a4ae51246 PMC346076 U.S.A.Hemin-independent control of globin synthesis in Friend erythroleukemia cells induced to differentiate. 1 IP:IPR000971 IP:IPR000971 activates MESH:D001284 Phenotype 0d437548-c469-11e5-9da3-001a4ae51247 24139948 Imbalances of globin chains cause hemolysis, which results in mild to severe anemia.1Patients with anemia may have atrophic glossitis (AG) or generalized oral mucosal atrophy and tenderness or burning sensation of oral mucosa.2However, it is still not known whether patients with thalassemia trait (TT including α- or β-thalassemia minor) may have specific oral manifestations and what percentages of TT patients may have the oral manifestations. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0042167 Phenotype ced70afc-bc1d-11e5-8abe-001a4ae51246 PMC4241286 This reaction leads to extensive cross-linking between the globin chains and oxidation of cysteine residues inβglobin protein, which further leads to heme degradation [37]. 1 IP:IPR000971 IP:IPR000971 activates GO:0015886 Phenotype ea83db3e-bc47-11e5-9b9d-001a4ae51247 10.1016/j.bbapap.2008.04.012 Relative importance of globin stability and heme transport A number of preliminary experiments have been carried out using thein vivoHbCO derivative assay to estimate the relative importance of globin stability and enhanced heme transport, and a sample of these results is shown inFig. 1 IP:IPR000971 IP:IPR000971 activates MESH:D012805 Phenotype 771f9ac2-bc22-11e5-8abe-001a4ae51246 PMC3407482 Homozygous expression of this mutant globin genotype (SS) causes SCD, while the heterozygous genotype (AS) is termed the “sickle cell trait” [1,2]. 1 IP:IPR000971 IP:IPR000971 inhibits GO:0006787 Phenotype d8e2ec6c-3756-11e8-b868-001a4a160176 25148987 These results are consistent with haemin released from the globin causing lipid oxidation and porphyrin degradation when considering both trout and bovine Hb; just that the onset of lipid oxidation was more rapid with the fish Hb due to its more rapid rate of haemin dissociation while the extents of lipid oxidation due to trout and bovine metHb were similar. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Ubiquitin ProteinFamily dfa36c3e-bc47-11e5-8abe-001a4ae51246 10.1016/j.bbapap.2011.03.007 They found that ubiquitin conjugation to globin was markedly enhanced by denaturation of hemoglobin and the concentration of globin–ubiquitin conjugates was proportional to the rate of hemoglobin degradation[60]. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Histone ProteinFamily 191c77de-3a8c-11e8-8f56-001a4a160175 28351005 Furthermore, we reported that AgNPs inhibited globin transcription through reducing the methylation status of histone in erythroid progenitor cells, highlighting an important role of epigenetic mechanisms in nanotoxicity[26]. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Histone ProteinFamily 789a7160-c47e-11e5-9cc6-001a4ae51246 PMC2837319 Therefore, these data suggest that the effects of PRMT1 KD on globin transcription are most likely due to reduced recruitment of PRMT1 and diminished histone modifications at the βmaj-promoter region. 1 IP:IPR000971 IP:IPR000971 activates PF:PF01877 ProteinFamily 1bbadf0a-cb29-11e5-a6cd-001a4ae51247 11418588 eIF4B is a dimeric protein (70-kDa subunit) that has no independent catalytic activity and functions to stimulate the RNA binding, ATPase, and helicase activities of eIF4A and eIF4F, as well as overall globin synthesis in fractionated lysate systems (13,16-19). 1 IP:IPR000971 IP:IPR000971 activates FPLX:CYP ProteinFamily 3a9dd9fe-ab16-11e6-81c1-001a4ae51246 PMC5095920 Introduction intro Haem is an important cofactor required for a variety of functions, including the transport of oxygen and carbon dioxide in multicellular organisms, cytochrome-mediated electron transfer in respiratory chains, and detoxification of nitric oxide by bacterial globin proteins. 1 IP:IPR000971 IP:IPR000971 activates FPLX:IL2R ProteinFamily fd326182-ca5d-11e5-9088-001a4ae51247 PMC1271653 The gene encoding the Tac subunit of the interleukin 2 receptor (IL2R) driven by an erythroid‐specific chicken βA‐globin promoter and the β/ε enhancer (Figure 3bottom line) was integrated into the early erythroid 6C2 cell line. 1 IP:IPR000971 IP:IPR000971 inhibits FPLX:GST ProteinFamily b32da774-c8df-11e5-9624-001a4ae51246 PMC1500856 To test this directly, the polyadenylation hexanucleotide in the GST β‐globin/PRE reporter mRNA was disrupted (AAUAAA to AAgAAA;Foxet al, 1989) to generate GST β‐globin/PRE/hex mt. 1 IP:IPR000971 IP:IPR000971 activates PF:PF16525 ProteinFamily e6667b16-bc14-11e5-8abe-001a4ae51246 10.1016/S0925-4773(01)00528-7 7Q,R, the globin-injected control embryo exhibited normalEn-2expression in the morphologically defined MHB region, whereas XHR1-VP16 diminishedEn-2expression and disrupted the morphological feature of the MHB on the gal-stained left side. 1 IP:IPR000971 IP:IPR000971 inhibits FPLX:Interferon ProteinFamily 95416026-bc31-11e5-9b9d-001a4ae51247 PMC3838409 A number of recent studies have successfully employed a CpG-depleted plasmid (pcpg-MCS; the same as that employed in this study) containing a human IFNβ S/MAR, in addition to a human ßGlobin S/MAR [24–26]. 1 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily 3b9eaf44-c468-11e5-9da3-001a4ae51247 23478515 The surrounding globin has been suggested to modulate the reactivity of heme and more specifically the reactivity of heme iron through the heme-globin interactions. 1 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily a9270856-5cbd-11e7-bcb7-001a4ae51246 26435388 The large entropy contribution structurally indicates that the heme rotation is induced by the concerted fluctuation of many heme–globin contacts within a small temperature range[17]. 1 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily c9e202aa-3532-11e8-8f56-001a4a160175 24188961 Co-overexpression of heme and globin constructs increased heterologous hemoglobin production The top three heme overexpression plasmids H3, H3H2H12 and H12 were selected to be co-transformed together with a range of globin overexpression plasmids B/A, B/AA, B/AA/B, B/A/A and the empty vector pSP-GM1 (Fig. 1B). 1 IP:IPR000971 IP:IPR000971 increases IP:IPR006361 ProteinFamily cf3158b0-c82e-11ee-ae05-0050569a1f61 PMC10329284 HRI knockout (KO) mice do not exhibit significant erythroid abnormalities under standard dietary condition.12However, when challenged with an iron-deficient diet, these mice develop a characteristic anemia with globin aggregation in red blood cells.12One potential explanation for these iron-dependentin vivoeffects is that iron deficiency concomitantly decreases heme levels, and this fall in heme is the mechanism of HRI activation. 1 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily a5bdbe26-4558-11f0-8978-0050569a1f61 PMC9185156 They include global and specific translation defects, cell-cycle perturbation, p53 activation, abnormal GATA1 expression, and the toxicity of excess heme caused by dyssynchronous globin synthesis.5Thus, which mechanism to address in order to permit the best therapeutic option is the subject of considerable thought. 1 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily 292e4b58-c468-11e5-91a7-001a4ae51247 PMC3648058 "In this study, we directly test the hypothesis that decreased globin chain production leads to increased free heme and early erythroid progenitor cell death by developing erythroid model systems that are devoid of all adult globin chains." 1 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily 4ef8a072-ca5d-11e5-8050-001a4ae51246 14634026 InReaction 2, the porphyrin radical dissipates in the globin, causing formation of amino acid radicals while leaving the heme moiety in a FeIV=O form similar to compound II (5–8). 1 IP:IPR000971 IP:IPR000971 increases IP:IPR006361 ProteinFamily a78f164a-c46c-11e5-a92e-001a4ae51246 24412987 Given a role for free heme in ROS production[33], dysregulation of FLVCR expression or perturbations in globin synthesis linked to ribosomal protein haploinsufficiency could increase intracellular heme levels and enhance ROS production in the developing erythron relative to other hematopoietic lineages. 1 IP:IPR000971 IP:IPR000971 increases IP:IPR006361 ProteinFamily 0368f4ce-0e67-11f0-b759-0050569a791b 10.1182/blood.V91.3.798 Erythroid cells synthesize a large amount of heme, which is several orders of magnitude greater than other cells,1and yet in normal erythroid cells, the amount of heme and globin is stoichiometrically matched. 1 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily 6051da68-bc4e-11e5-9b9d-001a4ae51247 PMC3360922 Liu et al. also recently demonstrated that macrophage maturation is perturbed in mice deficient in heme-regulated eIF2α kinase (HRI), a factor that inhibits globin synthesis in heme-limited erythroid precursors; mutant mice display impaired erythrophagocytosisin vitroandin vivoin conditions of chronic hemolytic anemia[85]. 1 IP:IPR000971 IP:IPR000971 decreases IP:IPR006361 ProteinFamily e9d1ecc0-bbdf-11e5-8abe-001a4ae51246 PMC3671302 This suggests that heme release is not impaired by covalent crosslinking of globin chains in ferrylHb. 1 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily 1ec7e32a-c73b-11ee-b22c-0050569a1f61 10.1016/j.jhazmat.2023.132124 We therefore proposed the hypothesis: Some specific globin protein mediating heme homeostasis signaling can be involved in controlling PS-NPs-induced transgenerational toxicity. 1 IP:IPR000971 IP:IPR000971 activates IP:IPR006361 ProteinFamily 7de7a164-3903-11e8-87fd-001a4a160176 22732165 Of note, the synthesis of heme (and indirectly globin) is in itself inhibited by cobalt (Co2+) that inhibits δ-aminolevulinic acid synthase and porphobilinogen synthase (or δ-aminolevulinic acid dehydratase) (see, e.g.Nakamura et al., 1975). 1 IP:IPR000971 IP:IPR000971 activates FPLX:Wnt ProteinFamily 7df3e8a8-f586-11eb-9383-001a4a160176 30638933 Sox6 also represses expression of embryonic globin genes in erythroid cells [12], and block canonical Wnt signaling in pancreatic β-cells through interaction with β-catenin [10]. 1 IP:IPR000971 IP:IPR000971 decreases IP:IPR001519 ProteinFamily 007bc562-c46a-11e5-8491-001a4ae51247 24511086 Differentiating FL/HO-1−/−cells show increased TfR and globin expression reduced ferritin expression As expected, we found that FL/HO-1−/−cells express higher amounts of TfR mRNA, in particular at 24 and 48 hours (Figure 5A), and exhibit a slight increase in TfR protein levels (Figure 5D-E). 1 IP:IPR000971 IP:IPR000971 activates PF:PF06745 ProteinFamily 1bbadf0a-cb29-11e5-a6cd-001a4ae51247 11418588 eIF4B is a dimeric protein (70-kDa subunit) that has no independent catalytic activity and functions to stimulate the RNA binding, ATPase, and helicase activities of eIF4A and eIF4F, as well as overall globin synthesis in fractionated lysate systems (13,16-19). 1 IP:IPR000971 IP:IPR000971 decreases IP:IPR000971 ProteinFamily 55533c56-5c43-11e7-8e96-001a4ae51246 PMC5394953 Bach1 controls heme and globin balance by directly repressing its targets The balance of heme and globin levels is critical for proper erythroid development.4Therefore, we considered whether the globin gene expression might be altered inBach1−/−mice under LID-DW. 1 IP:IPR000971 IP:IPR000971 decreases IP:IPR000971 ProteinFamily c7ec9678-96fc-11e8-9b5b-001a4a160175 PMC6021158 β-thalassemia is a hereditary disorder caused by defective globin production, resulting in abnormal as well as decreased quantity of globin chains. 1 IP:IPR000971 IP:IPR000971 increases IP:IPR000971 ProteinFamily 5c7249a4-c7ef-11ee-b346-0050569a791b 10.1016/j.gene.2023.147480 Ye et al. used the commercial liposome transfection reagent TurboFect to deliver CRISPR-Cas9 for deletion of the 13 k fragment in the β- globin gene, which ultimately increased the expression of the γ- globin gene (Ye et al., 2016). 1 IP:IPR000971 IP:IPR000971 increases IP:IPR000971 ProteinFamily 32add0f2-c465-11e5-a92e-001a4ae51246 PMC3811682 "However, miR-23a and miR-27a are not involved in the embryonic-to-fetal globin switching, because they promote the expression of both embryonic and fetal β-like globin genes." 1 IP:IPR000971 IP:IPR000971 decreases IP:IPR000971 ProteinFamily 0d35c498-bbf9-11e5-9b9d-001a4ae51247 10.1016/j.bcmd.2010.10.013 We speculated that the loss of embryonic globin gene induction could be explained by an inhibitor-mediated disruption of ongoing erythropoiesis, whether mediated through p38 or through other, non-p38 cellular targets, rather than through inhibitionper seof p38-mediated induction of embryonic/fetal globin gene expression. 1 IP:IPR000971 IP:IPR000971 increases IP:IPR000971 ProteinFamily 8486af26-3d13-11f0-afc2-0050569a791b PMC7483438 Along with limiting excess free heme, DBA erythroid cells also attempt to increase the level of globin chain translation by NRF2/Maf transcriptional activation of globin mRNA after BACH1 degradation and decreased EIF2α phosphorylation following inactivation and hypophosphorylation of HRI. 1 IP:IPR000971 IP:IPR000971 decreases IP:IPR000971 ProteinFamily a420860e-bbf4-11e5-8abe-001a4ae51246 PMC3836866 Furthermore, as none of the studies have attained a globin expression pattern resembling that of fetal liver derived erythrocytes, the mere downregulation of γ globin repressors without γ globin activators might not be sufficient to fully reactivate γ globin expression, and the activation might not be sustained over a prolonged period of time[48]. 1 IP:IPR000971 IP:IPR000971 activates IP:IPR000971 ProteinFamily 09f74f5c-bbfb-11e5-9b9d-001a4ae51247 PMC4121935 This mutation could be in the form of deletions, rearrangement of the loci or point mutations leading to impaired transcription, processing, or translation of globin mRNA, causing defective globin production. 1 IP:IPR000971 IP:IPR000971 increases IP:IPR000971 ProteinFamily 8af269a0-dc8d-11ea-a4b4-001a4a160175 PMC6123269 γ-to-β globin switching in neonatal period is driven by β-globin LCR, modulating β-like globin expressions by direct contact with their promoters. 1 IP:IPR000971 IP:IPR000971 decreases IP:IPR000971 ProteinFamily 1061aa92-bbf9-11e5-8abe-001a4ae51246 10.1016/j.bcmd.2011.10.003 During embryonic and fetal stage KLF1 levels are low resulting in low levels of adult beta globin, while in the adult high KLF1 expression induces elevated levels of adult beta globin and BCL11A, which in turn represses gamma globin expression[4,8,9]. 1 IP:IPR000971 IP:IPR000971 increases IP:IPR000971 ProteinFamily a3e37014-bbd8-11e5-8abe-001a4ae51246 PMC2228317 Multiple pathways control expression of the anoxia responsive globin genes Surprisingly, none of the HIF-1 responsive globin genes was induced whendaf-2(e1370)mutant animals were exposed to 12 h of oxygen deprivation (Table3). 1 IP:IPR000971 IP:IPR000971 increases IP:IPR000971 ProteinFamily 28c6d2a4-c47f-11e5-8491-001a4ae51247 PMC2957209 Treatment of hydroxyurea previously reported to increase γ‐globin transcription in K562 and primary erythroid cells (Tanget al, 2005) significantly increased the γ‐globin transcription in our cells (Supplementary Figure 11). 1 IP:IPR000971 IP:IPR000971 activates IP:IPR000971 ProteinFamily 0a8ccc48-ae94-11ec-ae7b-0050569a1f61 PMCPMC8589257 Inducing expression of fetal globin (γ-globin) gene expression to 60% to 70% of α-globin synthesis produces β-thalassemia trait globin synthetic ratios and has been shown to reduce anemia to mild levels that do not require regular blood transfusions. 1 IP:IPR000971 IP:IPR000971 increases IP:IPR000971 ProteinFamily c1af84ae-c473-11e5-9da3-001a4ae51247 PMC4475914 "The levels of these γ globin regulators have been previously demonstrated by others to modulate γ globin gene expression in either K562 cells or primary human erythroid cells (20–22,41)." 1 IP:IPR000971 IP:IPR000971 increases IP:IPR000971 ProteinFamily 8463ab9a-3520-11e9-8325-001a4a160175 29879440 In many cases, adult globin coexisted with abnormal expression of embryonic and fetal globin[48], demonstrating a trend toward decreasing embryonic and increasing fetal globin expression over time[49–53]. 1 IP:IPR000971 IP:IPR000971 increases IP:IPR000971 ProteinFamily d06b7072-ae94-11ec-89b1-0050569a791b PMCPMC8158146 Sinceβ–thalassemia patients lack β–globin chains, one of the most frequent mechanisms for restoring optimal oxygen-carrying status is to induce γ–globin expression to regain the generation of HbF tetramers (α2γ2) [9]. 1 IP:IPR000971 IP:IPR000971 increases IP:IPR000971 ProteinFamily 18895864-c8ec-11e5-9faa-001a4ae51247 PMC2643510 While the human γ globin mRNA levels represent the majority of all β-like globin gene expression during late fetal life, the percentage of total mouse α-like globin to total β-like globin mRNA increases during this period as the γ globin genes switch to the nonfunctional human β0globin genes that have a relatively short-lived mRNA (supplemental Table S1, Part B). 1 IP:IPR000971 IP:IPR000971 decreases IP:IPR000971 ProteinFamily 89e94154-c464-11e5-91a7-001a4ae51247 PMC3719677 "Thus, in primitive erythroid cells, KLF1 and KLF2 drive transcription of embryonic globin genes, while in definitive erythroid cells, KLF3 and KLF8 serve to repress embryonic globin expression." 1 IP:IPR000971 IP:IPR000971 inhibits IP:IPR000971 ProteinFamily 03c49450-c8e9-11e5-a1fd-001a4ae51246 18258918 Heme also initiates globin transcription through inhibiting the DNA binding of the repressor, Bach1 (1), and globin translation through inhibiting substrate phosphorylation by the repressor, erythroid-specific eukaryotic initiation factor 2α kinase (2). 1 IP:IPR000971 IP:IPR000971 decreases IP:IPR000971 ProteinFamily 613eaf4c-c9fe-11e5-be63-001a4ae51246 PMC528959 It was well known that, in mammals,GATA1is an activator of γ globin, and it also inhibits the expression of ε globin gene in the presence ofYY1, whereasKLF1enhances the expression of β globin gene. 1 IP:IPR000971 IP:IPR000971 activates FPLX:HIF ProteinFamily 0210539a-c47c-11e5-8491-001a4ae51247 21445847 The presence of putative hypoxia responsive elements in the genomic regions of all anoxia-induced globin genes further supports a HIF-dependent regulation. 1 IP:IPR000971 IP:IPR000971 activates FPLX:EIF4A ProteinFamily 1bbadf0a-cb29-11e5-a6cd-001a4ae51247 11418588 eIF4B is a dimeric protein (70-kDa subunit) that has no independent catalytic activity and functions to stimulate the RNA binding, ATPase, and helicase activities of eIF4A and eIF4F, as well as overall globin synthesis in fractionated lysate systems (13,16-19). 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 82f0f744-bbe9-11e5-8abe-001a4ae51246 PMC4213961 [1] The reduced supply of globin diminishes the production of hemoglobin tetramers, causing hypochromia and microcytosis. 1 IP:IPR000971 IP:IPR000971 inhibits FPLX:Hemoglobin ProteinFamily 46cad606-bc1e-11e5-9b9d-001a4ae51247 10.1016/j.jchromb.2010.04.017 Reduced synthesis of one of the globin chains can cause the formation of abnormal hemoglobin molecules, thus causing anemia, the characteristic presenting symptom of the thalassemia. 1 IP:IPR000971 IP:IPR000971 increases FPLX:Hemoglobin ProteinFamily 8eaae0e0-c775-11ee-b346-0050569a791b 10.1182/blood.2023021369 In most patients, clinical management still largely depends on supportive treatment with red blood cell transfusions and iron chelation.3Hydroxyurea is used to increase γ-globin expression as this fetal β-like globin combines with free α-globin to form fetal hemoglobin, increasing functional hemoglobin levels and reducing toxic levels of unpaired α-globin. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily e6fd1ab0-c463-11e5-85e4-001a4ae51246 23439662 "Collectively, M3 is the terminal product of BFBTS metabolism in rat blood, and rat RBCs are the only site where M3 is generated In Vitro Study of BFBTS-Induced Modification of Rat Hemoglobin ESI-TOF Analysis of Intact Globin." 1 IP:IPR000971 IP:IPR000971 increases FPLX:Hemoglobin ProteinFamily 399dfd5a-bc32-11e5-9b9d-001a4ae51247 PMC3704632 Balanced globin chain synthesis coupled with heme biosynthesis is required to produce sufficient quantities of hemoglobin for effective erythropoiesis[22]. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily f535e562-c47c-11e5-85e4-001a4ae51246 PMC2913073 This finding suggests that heme rather than the globin chains mediate the FPN1 response to hemoglobin. 1 IP:IPR000971 IP:IPR000971 inhibits FPLX:Hemoglobin ProteinFamily e6329fe8-ae94-11ec-b4ed-0050569a1f61 PMCPMC8793691 The use of whole transcriptome, non-ribosome/globin depleted RNA enables the identification of novel RNAs and the correlation to hemoglobin genes. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily d0187326-bc34-11e5-ac4e-001a4ae51246 PMC2668177 Two other hemoglobin genes, HBD and HBE, were also significantly down-regulated by globin reduction in both assays. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 97edc150-c47b-11e5-9cc6-001a4ae51246 21636714 The accumulation of globin messenger RNA, increased iron assimilation and heme biosynthesis, accumulation of hemoglobin, the emergence of erythrocyte membrane proteins, cell-cycle arrest, and accumulation of hyperacetylated histone. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 40307d5c-bbf9-11e5-9b9d-001a4ae51247 PMC3998052 It is plausible that the diversification of Atlantic cod globin has been driven by positive selection, since these non-synonymous mutations alter hemoglobin function and likely confer an adaptive advantage. 1 IP:IPR000971 IP:IPR000971 inhibits FPLX:Hemoglobin ProteinFamily aa39e81a-c8eb-11e5-a4c6-001a4ae51246 PMC2581980 In general, insufficiency of porphyrin, iron, or globin impairs hemoglobin production and results in a hypochromic, microcytic anemia.4,5 Heme, the prosthetic group of hemoglobin, is formed in a series of well-characterized catalytic steps that occur within and outside of mitochondria. 1 IP:IPR000971 IP:IPR000971 inhibits FPLX:Hemoglobin ProteinFamily e0fbba76-c875-11ee-b346-0050569a791b PMC10290944 β-thalassemia is a genetic hemoglobin disorder that results in anemia due to impaired hemoglobin production caused by an abnormal globin gene. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 91d473b4-bc00-11e5-9b9d-001a4ae51247 PMC3334423 In terminally differentiated anucleated erythrocytes, highly stable globin transcripts continue to synthesize globin protein to support the production of hemoglobin. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily f9d19dca-bc05-11e5-8abe-001a4ae51246 PMC3921875 Thalassemia is a chronic genetic blood disease induced by the deficiency of one or more chains of globin synthesis in hemoglobin molecule with symptoms such as: severe and chronic anemia, failure to thrive and hepatosplenomegaly, and bone disorders. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily e4f247d0-c956-11ee-b346-0050569a791b 10.1016/j.cca.2022.11.031 Co-elution of the glycated form of genetic variants of hemoglobin with the native form of HbA The mutation in the globin gene might increase the net surface positive charge of the tetrameric hemoglobin molecule, which results in an increase in the elution time of both the genetic variant as well as the glycated form of the variant hemoglobin. 1 IP:IPR000971 IP:IPR000971 inhibits FPLX:Hemoglobin ProteinFamily c50b047a-c478-11e5-91a7-001a4ae51247 21558467 "Butyrate stimulates production of fetal hemoglobin through induction of the fetal (γ) globin gene promoter, which thereby reduces globin chain imbalance in beta thalassemia, which in turn reduces anemia, or inhibition of polymerization of sickle hemoglobin; both effects ameliorate the clinical courses of the respective disease conditions (Steinberg and Rodgers 2001;Perrine 2005)." 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily ac216436-bbf4-11e5-8abe-001a4ae51246 10.1016/j.exphem.2004.05.024 Expression of globin genes within the β-globin cluster is regulated to produce different hemoglobin β chains during the embryonic (ε), fetal (γ), and adult (β) stages of erythroid cell development. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 4cefcadc-3533-11e9-913f-001a4a160175 PMC6001537 βS‐globin causes hemoglobin S (HbS) to form rigid polymers upon deoxygenation. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 47d884b4-8d97-11ee-add2-0050569a791b PMC9001768 Some mutations in the globin chains of Hgb raise the affinity of Hgb molecules for oxygen, which impairs the normal loading of oxygen in the lungs and the delivery of oxygen to tissues. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 5d862e44-c6c0-11ee-8b99-0050569a1f61 10.1016/j.lpm.2023.104214 The first in that sickle hemoglobin is caused by a monogenic point mutation in the beta globin gene that produces hemoglobin S which polymerizes and induces red blood cells sickling. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily e60461e2-bc05-11e5-8abe-001a4ae51246 10.1016/j.yexcr.2007.08.014 During development, different α- and β-like globin genes are coordinately regulated to produce embryonic, fetal and adult globin chains comprising developmental stage-specific hemoglobin molecules to carry oxygen[1]. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 0e9a32b6-bc52-11e5-8abe-001a4ae51246 10.1016/S0145-2126(02)00028-0 This concept has been used to increase expression of the gamma globin chain that results in increased fetal hemoglobin production. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 537653a0-bbf4-11e5-8abe-001a4ae51246 10.1016/j.cbpa.2012.09.001 Generally, specific amino acid substitutions in globin chains were thought to contribute to the adaptation to hypoxia, especially in birds such as bar-headed geese and Andean geese, where these substitutions increase oxygen affinity of hemoglobin (Hiebl et al., 1987; Jessen et al., 1991; Liu et al., 2001; McCracken et al., 2010). 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily f038a164-bc19-11e5-9b9d-001a4ae51247 PMC2764439 INTRODUCTION The α and β globin must be expressed at similar levels in erythrocytes to produce functional hemoglobin consisting of α2–β2tetramers; a failure to do so results in globin chain imbalances and the occurrence of thalassemias (1). 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 4b558c10-bbde-11e5-8abe-001a4ae51246 PMC3816679 Sickle Cell Anemia Sickle cell anemia (OMIM: 603903) or, otherwise, sickle cell disease (SCD), is a genetic disorder that results from a single point mutation (T to A) in the 17thnucleotide of the coding sequence (CDS) of the beta globin gene, producing the abnormal hemoglobin S (HbS: α2β2s) [64]. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 2945a19e-374e-11e8-a34b-001a4a160175 PMC7487207 In the most severe form of SCD, Sickle Cell Anemia, both beta globin genes carry the glu-val substitution at codon 6 of the beta globin locus causing hemoglobin S to be produced exclusively instead of the wild-type hemoglobin A1. 1 IP:IPR000971 IP:IPR000971 inhibits FPLX:Hemoglobin ProteinFamily e32f087c-c480-11e5-91a7-001a4ae51247 PMC2906581 "Abundant biochemical, epidemiological, and clinical evidence have shown that a high level of γ globin, the fetal form of β globin, inhibits the aberrant polymerization of sickle hemoglobin and ameliorates the disease phenotype (2)." 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily e4411476-3904-11e8-a34b-001a4a160175 28735981 Sickle-cell disease (SCD) is caused by an autosomal recessive mutation of theHBB(beta globin) gene leading to abnormality of β-globin chain, hemoglobin S (HbS), which polymerizes when deoxygenated, resulting in deformed and rigid erythrocytes. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 11a5ba82-bc27-11e5-8abe-001a4ae51246 10.1016/j.mehy.2011.07.037 The major thalassemia syndromes are of two groups – alpha and beta thalassemia depending on whether the alpha or beta globin chain synthesis of the adult hemoglobin is affected. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily df4a8940-c8e8-11e5-a1fd-001a4ae51246 PMC2278084 Under conditions of high-altitude hypoxia, adult alpacas (Vicugna pacos) and yaks (Bos grunniens) are known to upregulate a fetal β-like globin gene, which results in the synthesis of a relatively high-affinity fetal hemoglobin (Reynafarjeet al. 1975;Sarkaret al. 1999). 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 81817ffa-bbe9-11e5-9b9d-001a4ae51247 PMC3202272 [1] The reduced supply of globin diminishes the production of hemoglobin tetramers, causing hypochromia and microcytosis. 1 IP:IPR000971 IP:IPR000971 inhibits FPLX:Hemoglobin ProteinFamily 69f2e1de-bc3f-11e5-8d2d-001a4ae51247 PMC3220247 Thalassemia minor, which is very rare in Korea, involves genetically-determined abnormal globin chain synthesis that results in decreased hemoglobin production. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 940c12cc-ae93-11ec-89b1-0050569a791b PMCPMC8269253 Compared to those observed in HCs, the erythrocyte sedimentation rate (ESR), C-reactive proteins (CRP), granulocytes, neutrophils, platelet distribution width, total protein, globin, alkaline phosphatase, and γ-glutamyltransferase were increased, whereas the lymphocytes, eosinophils, mean erythrocyte hemoglobin concentration, mean platelet volume, direct bilirubin, indirect bilirubin, and creatinine levels were decreased in AS patients. 1 IP:IPR000971 IP:IPR000971 increases FPLX:Hemoglobin ProteinFamily 2dde46b8-c46c-11e5-8491-001a4ae51247 PMC4025059 In addition to HIFs as central components of the ATII cell response to hypoxia, our previous studies have clearly shown that hemoglobin is expressed by ATII cells and dramatically upregulated by HIF and globin-associated factors during hypoxia (7,24). 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 8eaae0e0-c775-11ee-b346-0050569a791b 10.1182/blood.2023021369 Although increasing β-like globin leads to increased functional hemoglobin, it is important not to overlook its role in reducing the excess of the free α-globin chains, which are the primary culprit in β-thalassemia pathology as they cause ineffective erythropoiesis. 1 IP:IPR000971 IP:IPR000971 activates FPLX:Hemoglobin ProteinFamily 01825a12-bbf9-11e5-8abe-001a4ae51246 10.1016/j.bcmd.2013.04.007 Introduction Both α- and β-globin gene clusters are commonly associated with hereditary disorders in humans: approximately 7% of the world's population carry globin gene mutation that leads to hemoglobin (Hb) gene disorder[1,2]. 1 IP:IPR000971 IP:IPR000971 decreases FPLX:FGF ProteinFamily b9518ed0-bc47-11e5-9b9d-001a4ae51247 PMC4050694 Then, by reducing FGF levels (10-40 pg RNA) and keeping Smad2C constant at 50 pg, globin expression was increased, and PGC markers were decreased. 1 IP:IPR000971 IP:IPR000971 activates FPLX:GPCR ProteinFamily b2f48d82-ab14-11e6-b3b6-001a4ae51247 PMC5133818 Another protein–protein interaction involving NGB has been suggested by experimental data showing that the globin modulates GPCR signaling [89] by interacting with the Gαsubunits of the trimeric G protein. 1 IP:IPR000971 IP:IPR000971 activates PF:PF12338 ProteinFamily 7cacde70-c914-11ee-9aaa-0050569a1f61 PMC9979759 The single point genetic mutation in the beta chain of globin (Glu6Val) causes the production of abnormal Hb (HbS) in sickle RBCs. 1 IP:IPR003132 activates IP:IPR000971 IP:IPR000971 ProteinFamily 773a525c-c8e5-11e5-9624-001a4ae51246 PMC1900146 Interestingly, protein A also increased the accumulation of globin mRNA, YFP mRNA, andDBP2mRNA (Fig.5A). 1 UNIPROT:P00387 inhibits IP:IPR000971 IP:IPR000971 Protein 8c5cdef4-c9c0-11ee-b22c-0050569a1f61 PMC9706631 Additionally, CYB5R3 also directly reduces myoglobin, a globin hemoprotein that possesses a reactive heme iron for binding oxygen and subsequent transport from the plasma membrane to the mitochondria in muscle fibers (85). 1 MESH:D000755 activates IP:IPR000971 IP:IPR000971 Phenotype 5bccf734-bc2b-11e5-9b9d-001a4ae51247 PMC183831 Sickle cell anemia (Hb SS) results from homozygosity for a A→T substitution at codon 6 of the β-globin gene (GAG→GTG) leading to a glutamic acid to valine (Glu→Val) substitution in the β globin chain of human adult hemoglobin. 1 MESH:D017086 increases IP:IPR000971 IP:IPR000971 Phenotype 5c34109c-c467-11e5-8491-001a4ae51247 24319154 "Beta-thalassemia erythroblasts are unable to produce adequate amounts of beta globin chains but synthesize normal amounts of alpha chains and heme." 1 CHEBI:17877 activates IP:IPR000971 IP:IPR000971 Chemical aeae2a90-bc03-11e5-9b9d-001a4ae51247 10.1016/j.fct.2009.05.015 At higher concentrations of the reducing agent the FDA adduct level decreased and eventually disappeared (at 1.5mg/mL) and the HMF adduct level increased to reach 200pmol/g globin (at 0.5–60mg NaBH3CN/mL). 1 UNIPROT:Q13351 increases IP:IPR000971 IP:IPR000971 Protein 8863ad52-3531-11e8-8f56-001a4a160175 24560123 The erythroid factors GATA-1, KLF-1, and NF-E2 that play a role in the decisions that lead to erythroid differentiation also regulate and coordinate globin gene transcription[81]. 1 UNIPROT:Q13351 activates IP:IPR000971 IP:IPR000971 Protein 7906c776-3406-11e8-9192-001a4a160175 PMC5807248 Since KLF1 preferentially activates adult globin genes[103,104], this MYB-KLF1-BCL11A-LRF regulatory circuit results in high-level expression of adult globin genes and very efficient repression of the embryonic/fetal genes in adult erythroid cells. 1 UNIPROT:Q13351 activates IP:IPR000971 IP:IPR000971 Protein f57cdc6a-5c3d-11e7-86a3-001a4ae51246 PMC5396323 KLF1‐Activated Erythroid Cells Express Embryonic Globins HPLC analyses of protein isolated from cells at day 31 of the differentiation protocol showed that activation of KLF1 in iKLF1.2‐derived erythroid cells significantly enhanced the proportion of the embryonic ε‐ and ζ‐globin and reduced the proportion of γ‐globin protein. 1 UNIPROT:Q13351 increases IP:IPR000971 IP:IPR000971 Protein d453006e-ae95-11ec-840e-0050569a791b PMCPMC8806501 Furthermore, some study has found that the expression of KLF1 increased the expression of fetal globin repressor Zinc Finger and BTB Domain Containing 7A (ZBTB7A) in erythroid cells [12]. 1 UNIPROT:Q13351 inhibits IP:IPR000971 IP:IPR000971 Protein a420860e-bbf4-11e5-8abe-001a4ae51246 PMC3836866 The reactivation of γ globin in adult erythroid cells in vitro and in vivo via knocking down γ globin repressors, such as Bcl11A and EKLF, is well documented[21,30,50]. 1 FPLX:CAPN decreases IP:IPR000971 IP:IPR000971 ProteinFamily 605a06f8-c472-11e5-9da3-001a4ae51247 PMC2740439 We next examined whether the specific inhibition of calpain is sufficient to induce globin gene expression in MEL cells. 1 CHEBI:17234 activates IP:IPR000971 IP:IPR000971 Chemical e766a3b8-bbf3-11e5-8abe-001a4ae51246 10.1016/j.ab.2013.07.016 High blood glucose concentrations promote the nonenzymatic posttranslational chemical modification of specific globin amino groups via the Maillard reaction. 1 CHEBI:17234 inhibits IP:IPR000971 IP:IPR000971 Chemical 563386be-ae94-11ec-ae7b-0050569a1f61 PMCPMC8780222 In contrast, the addition of glucose to Hb at final concentrations of 1, 5, 20, and 100 mM significantly decreased the formation of glycidol–Hb adduct (13.9-, 12.9-, 13.0-, and 11.1-μmol/g globin, respectively) (Figure 3A). 1 UNIPROT:P01241 activates IP:IPR000971 IP:IPR000971 Protein b1f4b6ec-bc3f-11e5-ac4e-001a4ae51246 10.1016/j.gene.2008.11.001 The identical translational IS used for the growth hormone was also used to enhance translation of the α globin. 1 UNIPROT:Q13547 activates IP:IPR000971 IP:IPR000971 Protein f3c371a8-c46e-11e5-9da3-001a4ae51247 PMC4003889 Additional studies have clarified that HDAC1 associated with NuRD is responsible for β globin gene activation but is dispensable for activation of γ globin (Miccio and Blobel, 2010) while HDAC3 associated with nuclear receptor co-repressor (NCoR) is responsible for suppressing expression of γ globin (Mankidy et al., 2006). 1 UNIPROT:Q10981 activates IP:IPR000971 IP:IPR000971 Protein 0a5cfa10-bbf0-11e5-9b9d-001a4ae51247 10.1016/j.ijbiomac.2010.11.002 Finally, sedimentation equilibrium data allowed to estimate theMof all four globin subunits,a,b,candd. 1 UNIPROT:O60675 inhibits IP:IPR000971 IP:IPR000971 Protein 6984533c-bc48-11e5-9b9d-001a4ae51247 10.1016/j.jprot.2012.12.014 We further found that KAP-1 may interact with MafK to negatively regulate β-major globin, and with Zfp445 to negatively regulate the embryonic Ey gene. 1 UNIPROT:P46100 increases IP:IPR000971 IP:IPR000971 Protein 69293c6b-dc36-11ea-891c-001a4a160176 PMC6476535 Knockout of atrx reduces globin expression and affects definitive erythropoiesis in zebrafish. 1 UNIPROT:P02042 activates IP:IPR000971 IP:IPR000971 Protein 79368134-8bfc-11e8-99e1-001a4a160175 30012865 At the adult stage, the HBD upstream elements contribute to the establishment of repressive chromatin containing the embryonic and fetal globin genes. 1 CHEBI:17296 increases IP:IPR000971 IP:IPR000971 Chemical 0dd458f0-c069-11e5-bf9a-001a4ae51246 PMC4454050 Castaneda et al. determined that short-chain fatty acids [arginine butyrate, sodium α-methylhydrocinnamate, sodium 2,2-dimethylbutyrate, sodium 3,4-(methylenedioxy) cinnamate, 2-(quinazolin-4-ylamino) butanoic acid, and 4-(trifluoromethyl) sulfanyl aniline acetic acid] increased the erythroid-BFU colonies and endogenous fetal globin gene expressions [5]. 1 UNIPROT:A5YKK6 inhibits IP:IPR000971 IP:IPR000971 Protein eeeda250-f459-11e5-95fd-001a4ae51246 PMC4888236 Likewise, in HEK293T cells, MS2‐tagged TNRC6A silencing domain (SD), AGO2, and NOT1 degraded a β‐globin reporter containing 6 binding sites for the MS2 protein in the 3′‐UTR (Fig2N, lanes 3, 5, and 7 versus 1). 1 CHEBI:46024 increases IP:IPR000971 IP:IPR000971 Chemical c1af84ae-c473-11e5-9da3-001a4ae51247 PMC4475914 "The activation of the p38 MAPK signaling pathway has been suggested to mediate the fetal γ globin gene expression in response to NaB or TSA treatment (23,24)." 1 CHEBI:46024 inhibits IP:IPR000971 IP:IPR000971 Chemical 12b886a0-cc8c-11e5-888a-001a4ae51246 PMC20860 "Butyrate and trichostatin A also reactivated a silenced globin gene construct that was stably transduced into K562 cells." 1 MESH:D020135 decreases IP:IPR000971 IP:IPR000971 Phenotype e05081bc-bc3d-11e5-8d2d-001a4ae51247 PMC3161909 A set of four peptide nucleic acid (PNA) oligomers whose sequences are complementary to the 3′ portions of the alpha and beta hemoglobin RNA transcripts were added to reduce globin RNA transcription due to RBC. 1 GO:0009058 activates IP:IPR000971 IP:IPR000971 Phenotype 2d344c3e-5c33-11e7-86a3-001a4ae51246 PMC5305046 The mRNAs carrying uORFs are enriched for factors with key roles in erythroid maturation, including the basic-helix-loop-helix transcriptional regulator Tal1 and the globin-switching effector Bcl11a.6Translation of theTal1uORF promotes synthesis of a truncated Tal1 protein isoform that favors erythroid lineage choice.7The demonstration that uORFs are common among the developmentally regulated genes in erythropoiesis supports the idea that uORFs may help tightly regulate the synthesis of key proteins that specify cell fate. 1 UNIPROT:P32780 increases IP:IPR000971 IP:IPR000971 Protein 3ff046b0-351e-11e8-9192-001a4a160175 PMC5886110 In terminally differentiated red blood cells, TTD-specific TFIIH mutations may cause imbalanced globin mRNA expression, explaining the relatively frequent anemic features of TTD (1,8). 1 UNIPROT:O94856 increases IP:IPR000971 IP:IPR000971 Protein b9fd5750-cc9c-11e5-888a-001a4ae51246 PMC1169765 Conversely, reduction of NF‐E2 in MEL cells inhibits globin expression (Kotkow and Orkin, 1995). 1 UNIPROT:O75444 increases IP:IPR000971 IP:IPR000971 Protein 8486af26-3d13-11f0-afc2-0050569a791b PMC7483438 Along with limiting excess free heme, DBA erythroid cells also attempt to increase the level of globin chain translation by NRF2/Maf transcriptional activation of globin mRNA after BACH1 degradation and decreased EIF2α phosphorylation following inactivation and hypophosphorylation of HRI. 1 UNIPROT:Q6PF39 activates IP:IPR000971 IP:IPR000971 Protein 084d73c0-d5ae-11e6-a821-001a4ae51247 PMC5314177 "Previous reports have revealed that AML causes defects in granulocytic differentiation caused by mutations in cell differentiation-promoting transcription factors, such as CCAAT/enhancer-binding protein α (C/EBPα), PU.1, and globin transcription factor-1 (GATA-1) (16–18)." 1 FPLX:Cohesin activates IP:IPR000971 IP:IPR000971 ProteinFamily ff188f00-bc46-11e5-8d2d-001a4ae51247 PMC2856913 These results suggest a cell type– and locus-specific chromatin organization supported by cohesin and CTCF at the globin locus. 1 MESH:D013789 increases IP:IPR000971 IP:IPR000971 Phenotype 1706f658-bc27-11e5-8abe-001a4ae51246 10.1016/j.mehy.2009.12.010 Thalassemias occurs due to a large number of different mutations causing abnormal globin gene expression and resulting in total absence or reduction of globin chain synthesis[51]. 1 MESH:D013789 increases IP:IPR000971 IP:IPR000971 Phenotype 2e5d1c8d-f58b-11eb-94cf-001a4a160176 30792169 HbF induction Thalassemia patients with persistently high levels of fetal globin typically have less severe anemia, have milder clinical syndromes, and are often transfusion independent [17]. 1 MESH:D013789 increases IP:IPR000971 IP:IPR000971 Phenotype a98ab0be-bc09-11e5-8abe-001a4ae51246 PMC3033156 ß-thalassemia, sickle cell anemia and other hemoglobinopathies: The thalassemias are a group of disorders due to a large number of heterogeneous mutations causing abnormal globin gene expression resulting in the total absence or quantitative reduction of globin chain synthesis1. 1 MESH:D013789 inhibits IP:IPR000971 IP:IPR000971 Phenotype cd645424-c463-11e5-9cbe-001a4ae51247 PMC3552344 "THE THALASSEMIA SYNDROMES The thalassemia syndromes are inherited disorders characterized by absence or markedly decreased accumulation of one of the globin subunits of hemoglobin." 1 UNIPROT:P49711 activates IP:IPR000971 IP:IPR000971 Protein ff188f00-bc46-11e5-8d2d-001a4ae51247 PMC2856913 These results suggest a cell type– and locus-specific chromatin organization supported by cohesin and CTCF at the globin locus. 1 UNIPROT:Q9Y5W3 increases IP:IPR000971 IP:IPR000971 Protein 95f5f06a-c481-11e5-8491-001a4ae51247 PMC3434496 "While KLF1 and KLF2 have been shown to directly stimulate globin gene expression in primitive erythroid cells, Myc may potentially influence hemoglobin production indirectly, by modulating heme synthesis or iron-controlling genes (54,79)." 1 UNIPROT:Q9Y5W3 activates IP:IPR000971 IP:IPR000971 Protein 89e94154-c464-11e5-91a7-001a4ae51247 PMC3719677 "Lastly, it should be noted that although KLF1 and KLF2 have both been shown to directly bind to the promoters of the embryonic globin genes, we have thus far not detected KLF3 occupancy at these sites (Fig. 6)." 1 UNIPROT:Q9Y5W3 increases IP:IPR000971 IP:IPR000971 Protein 0d772d70-bbf9-11e5-8abe-001a4ae51246 PMC3150518 KLF2 positively regulates the expression of the mouse and human embryonic globin genes[20]. 1 FPLX:NFE increases IP:IPR000971 IP:IPR000971 ProteinFamily 70c5864e-cb29-11e5-a6cd-001a4ae51247 PMC59778 "By analogy to other transcription factors, the ability of NF-E2 to activate globin gene expression is likely to depend on discrete domains that mediate DNA binding and transcriptional activation." 1 FPLX:NFE increases IP:IPR000971 IP:IPR000971 ProteinFamily 0973c0b4-c480-11e5-9da3-001a4ae51247 PMC2871457 The CB3/NF-E2 cells expressed relatively high levels of the adult βmaj-globin gene in the absence of DMSO induction (Fig. 1F) but failed to increase globin gene expression in response to DMSO (data not shown). 1 FPLX:NFE increases IP:IPR000971 IP:IPR000971 ProteinFamily 8863ad52-3531-11e8-8f56-001a4a160175 24560123 The erythroid factors GATA-1, KLF-1, and NF-E2 that play a role in the decisions that lead to erythroid differentiation also regulate and coordinate globin gene transcription[81]. 1 UNIPROT:Q01130 activates IP:IPR000971 IP:IPR000971 Protein 2b08e104-c8e6-11e5-9624-001a4ae51246 PMC2223418 "Our observations that caffeine induces SC35 (Fig.7B), SC35 overexpression leads to CafRE-dependent cryptic exon inclusion in the context of the KLF6 gene as well as in a heterologous globin gene construct (Fig.8), and overexpression of SC35 results in increased complex formation at the CafRE in vitro (Fig.8D) allow us to extend our model to state that caffeine regulates the CafRE-dependent induction of SpKLF6, at least in part, by inducing the expression of SC35, thereby altering the activator/repressor ratio." 1 UNIPROT:P17509 decreases IP:IPR000971 IP:IPR000971 Protein 36205649-dbbd-11ea-a002-001a4a160175 PMC7486193 "Considering the principal role of HOXB6 in the HSC self-renewal and differentiation (Bhatlekar et al., 2018), and the fact that the HOXB6 protein repressed globin transcript levels in a DNA binding-dependent manner, thus repressing the erythroid phenotype in human leukemic cells (Shen et al., 2004), we investigated the effects of HOXB6 on SOX9 expression and properties of SOX9+ LPCs." 1 UNIPROT:Q9NR23 decreases IP:IPR000971 IP:IPR000971 Protein 935dccd4-ca02-11e5-be63-001a4ae51246 16339188 "Analysis of molecular markers by RT-PCR in these explants agreed with the conclusion that GDF3 has dorsalizing activity in the mesoderm, as GDF3 protein decreased the expression of the ventral mesodermal marker globin and induced the expression of dorsal paraxial markers such as muscle actin in the VMZ explants (see Fig. S1 in thesupplementary material)." 1 CHEBI:30751 increases IP:IPR000971 IP:IPR000971 Chemical a609d0c4-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2008.06.014 Based on experiments that predated the identification of butyrate as an inducer of HbF[81–83], it was initially proposed that this and related SCFAs induced fetal globin gene expression through HDAC inhibition, resulting in global histone hyperacetylation, including nucleosomes at the γ-globin promoters[69]. 1 CHEBI:30751 activates IP:IPR000971 IP:IPR000971 Chemical c1af84ae-c473-11e5-9da3-001a4ae51247 PMC4475914 "Several short-chain fatty acid (SCFA) derivatives that are able to induce γ globin have been identified by one of these studies (48)." 1 FPLX:Protease inhibits IP:IPR000971 IP:IPR000971 ProteinFamily 18451434-bc1b-11e5-8abe-001a4ae51246 10.1016/j.ejmech.2009.02.024 The other plasmepsins, as well as plasmepsin-1 and plasmepsin-2, and the falcipains (cysteine proteases) are then able to further degrade these large globin fragments. 1 MESH:D009569 increases IP:IPR000971 IP:IPR000971 Phenotype 14f08d0c-bc40-11e5-8d2d-001a4ae51247 PMC3820574 In this model, increased NO removal would decrease prolyl hydroxylase inhibition, destabilize Hif-1α, and attenuate globin expression and NO removal. 1 MESH:D009569 activates IP:IPR000971 IP:IPR000971 Phenotype 4b0cf66e-c8ed-11e5-b79b-001a4ae51246 PMC2481313 "It has been reported that NO•may act as an antioxidant, inhibiting ferryl myoglobin induced oxidative damage and globin radical catalyzed oxidation reactions (39)." 1 MESH:D008934 increases IP:IPR000971 IP:IPR000971 Phenotype 28531992-c473-11e5-91a7-001a4ae51247 PMC2745848 In experimental models, activation of mitogen-activated protein (MAP) kinase11and cyclic nucleotide pathways (cyclic guanosine monophosphate12,13and cyclic adenosine monophosphate)14modulate globin gene expression to some degree. 1 FPLX:HIF1 increases IP:IPR000971 IP:IPR000971 ProteinFamily 1afb7b2a-cbf0-11e5-83a8-001a4ae51246 9973316 "On the other hand, one might postulate that HIF-1 binds directly to a putative HIF-1 binding site present in the locus control region or promoters of the β-globin cluster, thereby repressing embryonic globin expression and/or activating fetal/adult globin expression." 1 UNIPROT:P01308 decreases IP:IPR000971 IP:IPR000971 Protein 47919678-7611-11ee-add2-0050569a791b 10.1007/s00418-023-02188-3 Insulin affects the theca cells and raises androgen levels, thus reducing the release of sex hormone-binding globin in the liver, and the level of free testosterone gradually increases as a result (Dumesic et al.2008; McNeilly and Duncan 2013). 1 UNIPROT:P01308 activates IP:IPR000971 IP:IPR000971 Protein 1d8d9db4-c47a-11e5-85e4-001a4ae51246 21245462 Briefly, a 650-bpHindIII/BamHI fragment containing Reg3β cDNA from pBluescript II SK vector was subcloned into theEcoRI site downstream of insulin promoter in the pKS-RIP-I/globin vector, which contained a SV40 poly(A) signal (Fig. 1) (56). 1 UNIPROT:P27958 increases IP:IPR000971 IP:IPR000971 Protein 6e583cda-c8e0-11e5-9624-001a4ae51246 PMC1538551 NF‐E2 is necessary for globin gene expression in differentiated MEL (mouse erythroleukemia) cells but p45 KO mice exhibit only mild effects on erythropoiesis and no significant influence on globin gene expression (Shivdasani and Orkin, 1995). 1 UNIPROT:P05198 inhibits IP:IPR000971 IP:IPR000971 Protein 91d473b4-bc00-11e5-9b9d-001a4ae51247 PMC3334423 This process requires the heme-regulated inhibitor (HRI), a kinase that phosphorylates eIF2α to inhibit the translation of globin proteins when intracellular free heme is limiting[1]. 1 UNIPROT:P12270 increases IP:IPR000971 IP:IPR000971 Protein 2caaabb0-ae94-11ec-ae7b-0050569a1f61 PMCPMC8548687 In addition, TPR knockdown in human K562 cells also disrupted erythroid differentiation and dramatically elevated the expression of globin genes, which suggests that the functions of TPR in erythropoiesis are highly conserved in vertebrates. 1 UNIPROT:P39019 increases IP:IPR000971 IP:IPR000971 Protein 4bdde52e-c774-11ee-b346-0050569a791b PMC10469080 Thus, surviving DBA cells (trajectory A) downregulate heme production and upregulate globin transcription. 1 FPLX:Activin:A increases IP:IPR000971 IP:IPR000971 ProteinFamily 143a36b8-c467-11e5-a92e-001a4ae51246 24336657 Therefore, we used this cell line to study the molecular mechanism of the IFN-γ-inhibited activin A induction of globin expression. 1 UNIPROT:Q14839 inhibits IP:IPR000971 IP:IPR000971 Protein bd725f36-bbe2-11e5-9b9d-001a4ae51247 PMC3557762 A related protein, CHD4, has been shown to contribute to repression of lymphoid and erythroid lineage genes in mouse hematopoietic stem cells[13]and to repression of embryonic and fetal globin genes in human adult erythroid cells[14]. 1 UNIPROT:Q15723 inhibits IP:IPR000971 IP:IPR000971 Protein 0b452f4e-ae95-11ec-840e-0050569a791b PMCPMC8536016 The activated kinase phosphorylates elF2α to inhibit translation of certain mRNAs (especially globin) and enhance translation of other mRNAs (such as ATF4). 1 UNIPROT:Q9H165 increases IP:IPR000971 IP:IPR000971 Protein 9442e736-04bf-11f0-bb39-0050569a791b 10.1016/j.exphem.2024.104286 A therapeutic strategy was innovated involving CRISPR/Cas9- or precision base editing-mediated disruption of an erythroid-specific transcriptional enhancer [24] governing BCL11A expression, which reduces BCL11A expression and elevates fetal globin expression [25-29]. 1 UNIPROT:Q9H165 inhibits IP:IPR000971 IP:IPR000971 Protein a420860e-bbf4-11e5-8abe-001a4ae51246 PMC3836866 When these hybrid cells were induced in the presence of HDAC inhibitor decitabine, a more prominent effect of γ globin reactivation was observed in cells transduced with Bcl11A shRNA compared to cells transduced with the scrambled shRNA construct, suggesting a synergistic effect between HDAC inhibitor decitabine and γ globin repressor Bcl11A to bring about the induction of γ globin expression. 1 UNIPROT:Q9H165 inhibits IP:IPR000971 IP:IPR000971 Protein 9442e736-04bf-11f0-bb39-0050569a791b 10.1016/j.exphem.2024.104286 Human genetic, molecular, and biochemical studies revealed the transformative discovery of the fetal globin repressor BCL11A [20-23], which is central to the existing paradigm of how fetal β-like globin genes are repressed during development and how fetal globin gene de-repression counteracts the pathogenic consequences of mutant β-globin in sickle cell disease or insufficient β-globin in thalassemia. 1 UNIPROT:Q9H165 decreases IP:IPR000971 IP:IPR000971 Protein a420860e-bbf4-11e5-8abe-001a4ae51246 PMC3836866 As there were no differences in the levels of several known fetal γ globin repressors such as EKLF and Bcl11A, or activators such as KLF11 and HDAC9 in the γ globin–expressing versus β globin–expressing hybrids, the differential γ globin expression was unlikely to be dependent on these factors. 1 UNIPROT:Q9H165 activates IP:IPR000971 IP:IPR000971 Protein 34e4320a-31c5-11e9-9b28-001a4a160176 PMC6377191 The complete failure in the protein–protein complex interaction and significant changes in the interface energy with functional partners such as KLF1, HBB, HBG, HBA1, or NR2F revealed that rs61742690 (S783N) in the zinc-finger domain is a suitable target for disrupting BCL11A-mediated foetal-to-adult globin switching. 1 UNIPROT:Q9H165 inhibits IP:IPR000971 IP:IPR000971 Protein 7514367c-9516-11e9-922a-001a4a160176 PMC5889339 In contrast, other domains, including ZnF0 and ZnF1, appear dispensable for BCL11A-mediated globin repression (Figures 1C, 1D, andS1). 1 CHEBI:17245 increases IP:IPR000971 IP:IPR000971 Chemical bd0f744a-3406-11e8-9192-001a4a160175 28347842 Furthermore, CO is necessary for the transcription of the globin gene[6]. 1 UNIPROT:P01033 activates IP:IPR000971 IP:IPR000971 Protein 40e8e044-c691-11ee-ae05-0050569a1f61 10.1016/j.exphem.2023.11.002 Effects of the BNT162b2 Vaccine on EPO-Mediated Induction of Globin Genes: Evidence for Preferential Effects on HbF Production and Expression of γ-Globin Genes Panels A and B ofFigure 4show HPLC results obtained using ErPCs from patient #1, either untreated (Figure 4A) or treated with 1 μg/mL BNT162b2 (Figure 4B). 1 UNIPROT:P01033 increases IP:IPR000971 IP:IPR000971 Protein 0fcbf890-bc52-11e5-9b9d-001a4ae51247 10.1016/j.leukres.2010.07.033 Epo induces globin gene expression and specifically promotes late erythroid differentiation, cooperating with GATA-1, a transcription factor that plays a critical role in erythroid development. 1 UNIPROT:P01033 activates IP:IPR000971 IP:IPR000971 Protein 62681520-3757-11e8-87fd-001a4a160176 27283485 We speculate that the highest level of Hb in the combination- treated mice can be attributed to the higher number of reticulocytes induced by Epo together with globin and heme which were elevated by butyric acid and ALA, released from AN233, respectively. 1 UNIPROT:P01033 increases IP:IPR000971 IP:IPR000971 Protein 1d599dfe-d9fa-11ee-9133-0050569a1f61 10.1182/blood.V92.4.1104 Consistent with the notion that Epo can specifically promote at least certain late erythroid differentiation events, in several murine,16-18human,19and avian20cell lines, Epo has been shown to induce globin gene expression. 1 MESH:D012509 activates IP:IPR000971 IP:IPR000971 Phenotype ffd35214-d5fe-11e5-81c0-001a4ae51246 PMC388742 Our evidence shows that the globin genes activated by Rous sarcoma virus are those specified by embryonic chick red cells; adult-specific globin sequences were not detected. 1 MESH:D017382 increases IP:IPR000971 IP:IPR000971 Phenotype 3cb4e09e-b33c-11ee-bde4-0050569a1f61 PMC7229055 Furthermore, in vitro experiments have suggested that this drug induces the expression of Gamma Globin chains through increased reactive oxygen species-mediated p38 MAPK signaling and histone H 4 acetylation [15]. 1 MESH:D007501 activates IP:IPR000971 IP:IPR000971 Phenotype 903d99ea-c8e9-11e5-9624-001a4ae51246 PMC2555993 For example, iron promotes globin production by regulating activity of the heme-regulated inhibitor kinase, HRI, which inactivates the general translation initiation factor elF2 (16). 1 UNIPROT:O15245 decreases IP:IPR000971 IP:IPR000971 Protein d4b26162-c8eb-11e5-a801-001a4ae51246 PMC2544546 For example, Oct-1 together with the GATA-1 protein represses transcription of the human fetal globin genes in adults (27,28). 1 UNIPROT:O15266 activates IP:IPR000971 IP:IPR000971 Protein 5bccf734-bc2b-11e5-9b9d-001a4ae51247 PMC183831 Sickle cell anemia (Hb SS) results from homozygosity for a A→T substitution at codon 6 of the β-globin gene (GAG→GTG) leading to a glutamic acid to valine (Glu→Val) substitution in the β globin chain of human adult hemoglobin. 1 CHEBI:64103 activates IP:IPR000971 IP:IPR000971 Chemical 75c48052-d1df-11e5-aade-001a4ae51247 PMC345346 U.S.A.Activation of a chicken embryonic globin gene in adult erythroid cells by 5-azacytidine and sodium butyrate. 1 UNIPROT:Q92900 inhibits IP:IPR000971 IP:IPR000971 Protein e01c3cda-bc2f-11e5-ac4e-001a4ae51246 10.1016/j.febslet.2010.01.003 Notably, downregulation of eIF4AIII, Upf1, Upf2, or Y14 abrogated the NMD of globin (Gl) mRNA and glutathione peroxidase 1 (GPx1) mRNA harboring PTC by 2–5-fold (Supplementary Fig. S1), suggesting that all tested proteins were downregulated enough to abrogate NMD under our conditions. 1 UNIPROT:Q9HAU5 inhibits IP:IPR000971 IP:IPR000971 Protein e01c3cda-bc2f-11e5-ac4e-001a4ae51246 10.1016/j.febslet.2010.01.003 Notably, downregulation of eIF4AIII, Upf1, Upf2, or Y14 abrogated the NMD of globin (Gl) mRNA and glutathione peroxidase 1 (GPx1) mRNA harboring PTC by 2–5-fold (Supplementary Fig. S1), suggesting that all tested proteins were downregulated enough to abrogate NMD under our conditions. 1 CHEBI:26764 increases IP:IPR000971 IP:IPR000971 Chemical 017c8f3e-c47c-11e5-a92e-001a4ae51246 21445843 These results represent the first evidence for steroid hormone modulation of globin levels in cells (104). 1 UNIPROT:Q6ZN17 increases IP:IPR000971 IP:IPR000971 Protein 9ae7acf0-5c6d-11e7-9fde-001a4ae51247 PMC4986532 Ectopic expression of Lin28b in adult hematopoietic tissues confers fetal-like lymphoid differentiation (Yuan et al., 2012; Zhou et al., 2015), induces fetal globin expression (Lee et al., 2013), and promotes fetal-like self-renewal capabilities in HSCs (Copley et al., 2013). 1 UNIPROT:P13056 decreases IP:IPR000971 IP:IPR000971 Protein f51fff6c-c47d-11e5-9cc6-001a4ae51246 PMC3024783 The TR2/TR4 heterodimer binds to direct repeats of DNA elements in the embryonic and fetal globin gene promoter and represses globin gene transcription (10,11). 1 UNIPROT:P13056 decreases IP:IPR000971 IP:IPR000971 Protein 88411170-c8e6-11e5-a1fd-001a4ae51246 PMC1864974 To test the hypothesis that TR2/TR4 might negatively regulate embryonic and fetal globin gene transcription, we first asked which of these promoter DR elements could bind to DRED. 1 UNIPROT:P13056 decreases IP:IPR000971 IP:IPR000971 Protein 09e6db50-bc3b-11e5-8abe-001a4ae51246 PMC3814094 The orphan receptors TR2 and TR4 are thought to suppress the expression of embryonic globin genes. 1 CHEBI:29312 increases IP:IPR000971 IP:IPR000971 Chemical 0dd458f0-c069-11e5-bf9a-001a4ae51246 PMC4454050 Castaneda et al. determined that short-chain fatty acids [arginine butyrate, sodium α-methylhydrocinnamate, sodium 2,2-dimethylbutyrate, sodium 3,4-(methylenedioxy) cinnamate, 2-(quinazolin-4-ylamino) butanoic acid, and 4-(trifluoromethyl) sulfanyl aniline acetic acid] increased the erythroid-BFU colonies and endogenous fetal globin gene expressions [5]. 1 UNIPROT:Q9R0U0 activates IP:IPR000971 IP:IPR000971 Protein 591a0596-bc02-11e5-8abe-001a4ae51246 10.1016/j.niox.2010.12.009 In summary, Ctb is a truncated globin whose synthesis is upregulated by NssR on exposure ofC. 1 UNIPROT:P05763 increases IP:IPR000971 IP:IPR000971 Protein 5b0e09f8-cb28-11e5-8189-001a4ae51246 PMC86926 "HS3 can also enhance expression of globin genes, with its major function seen after integration." 1 UNIPROT:Q09472 decreases IP:IPR000971 IP:IPR000971 Protein c5a5aeae-ca5d-11e5-9bd2-001a4ae51247 PMC141148 "In agreement with this model, interference with CBP/p300 function through forced expression of the adenoviral protein E1A inhibited erythroid cell differentiation and globin gene expression (4)." 1 IP:IPR006361 activates IP:IPR000971 IP:IPR000971 ProteinFamily 62681520-3757-11e8-87fd-001a4a160176 27283485 In addition, heme increases Hb production by enhancing globin mRNA translation (Liu et al., 2007; Chiabrando et al., 2014). 1 IP:IPR006361 activates IP:IPR000971 IP:IPR000971 ProteinFamily e3a5c0b6-37ad-11e6-9aa8-001a4ae51247 PMC4816175 Toxicity of free heme has been mainly attributed to its pro-oxidative nature, which may either directly damage cells or may promote generation of toxic lipid-oxidation products.22,23,24,25,26,27Several pathways of renal tubule cell death may be relevant to AKI and renal failure following sustained exposures to Hb and its components (globin, heme, and iron). 1 IP:IPR006361 activates IP:IPR000971 IP:IPR000971 ProteinFamily cfd238ce-5c16-11e7-9833-001a4ae51246 PMC5500795 Fe3+-heme complex leads to an increase in absorbance at 408 nm, indicative of heme competition and binding to globin (Fig. 6C). 1 IP:IPR006361 inhibits IP:IPR000971 IP:IPR000971 ProteinFamily eabeb2b8-ca02-11e5-ab20-001a4ae51246 PMC1140573 "Heme-regulated eIF2α kinase (HRI) phosphorylates and inactivates eukaryotic initiation factor 2α (eIF2α) in the absence of heme (3), thereby coordinating heme and globin synthesis (11)." 1 IP:IPR006361 increases IP:IPR000971 IP:IPR000971 ProteinFamily eaa3ee78-c46d-11e5-91a7-001a4ae51247 PMC4040894 It has been reported that heme activates globin transcription by inhibiting the binding activity of BACH1 to the MARE sites in the locus control region of globin genes.52,53 In addition, heme also controls the transcription of other ubiquitously expressed genes, like the heme degrading enzyme heme-oxygenase-1,50the iron storage proteins Hand L-ferritin51and the iron exporter ferroportin.54The role of heme-oxygenase1 during erythroid differentiation is still controversial. 1 IP:IPR006361 activates IP:IPR000971 IP:IPR000971 ProteinFamily 5c306e30-bc36-11e5-8d2d-001a4ae51247 PMC4624791 As active HRI inhibits the eIF2α translation initiation factor, excess heme increases globin synthesis, allowing a better balance between heme and globin chains[38]. 1 IP:IPR006361 decreases IP:IPR000971 IP:IPR000971 ProteinFamily c80b068c-ae93-11ec-8b2e-0050569a1f61 PMC8387770 In erythroid cells, when iron and thus heme synthesis are sufficient, BACH1 is inactivated by heme, leading to the expression of globin genes and abundant synthesis of hemoglobin (20,60). 1 IP:IPR006361 increases IP:IPR000971 IP:IPR000971 ProteinFamily 62fbee56-c7a9-11ee-8b99-0050569a1f61 10.1016/j.aquaculture.2023.739525 Heme rapidly induces globin transcription and translation by removing Bach1 and inhibiting HRI activity(Doty et al., 2019). 1 IP:IPR006361 activates IP:IPR000971 IP:IPR000971 ProteinFamily 903d99ea-c8e9-11e5-9624-001a4ae51246 PMC2555993 Heme, which is produced when iron is replete, binds and inactivates HRI, enhancing globin translation. 1 IP:IPR006361 activates IP:IPR000971 IP:IPR000971 ProteinFamily 89c56048-c46b-11e5-85e4-001a4ae51246 PMC4300761 "HRI is activated by heme deficiency to prevent the synthesis of globin peptides in response to elevated heme levels." 1 IP:IPR006361 inhibits IP:IPR000971 IP:IPR000971 ProteinFamily 39e9e398-5ca7-11e7-af4d-001a4ae51247 PMC5290819 Although heme downregulates the globin gene repressor Bach1 [5], [17], [18], whether heme has a vital role in establishing/maintaining the erythroid transcriptome is unknown. 1 IP:IPR006361 decreases IP:IPR000971 IP:IPR000971 ProteinFamily 55533c56-5c43-11e7-8e96-001a4ae51246 PMC5394953 In wild-type erythroblast, the heme concentration is decreased when iron is low, leading to the activation of Bach1, and thereby an inhibition of globin genes andHmox1transcription (Figure 7G). 1 IP:IPR006361 increases IP:IPR000971 IP:IPR000971 ProteinFamily cfad98c6-cc1a-11e5-a19a-001a4ae51247 PMC108966 "For example, heme stimulates the expression of globin chains in erythroid cells and cytochrome P-450 in hepatic cells (6,9,36), activates protein synthesis through the heme-regulated inhibitor kinase (7), and regulates the transport of numerous enzymes and the assembly of hemoglobin and cytochrome complexes (24,31)." 1 IP:IPR006361 increases IP:IPR000971 IP:IPR000971 ProteinFamily 3f1baa50-c468-11e5-8491-001a4ae51247 PMC3658166 "Heme induces expression of globin genes in erythrocyte progenitor cells and thus plays an important role in erythropoiesis (12,25,26)." 1 PF:PF12417 decreases IP:IPR000971 IP:IPR000971 ProteinFamily 32add0f2-c465-11e5-a92e-001a4ae51246 PMC3811682 "SP1 is a ubiquitously expressed zinc finger protein that has been reported to repress β-like globin gene transcription through binding to HS1, HS2, HS3, HS4, HS5, and regions of the ε-, γ-, and β-globin gene promoter during Aγ181 cell erythroid differentiation (15) (Fig. 5G)." 1 UNIPROT:Q13422 increases IP:IPR000971 IP:IPR000971 Protein b3a66e14-c8eb-11e5-a801-001a4ae51246 18767169 Expression of a dominant negative version of Ikaros in primary human cells decreases the expression of both the fetal and adult globin genes, but more interestingly, strongly alters the ratio between γ- and β-gene expression in favor of the γ-globin genes (44). 1 UNIPROT:Q13422 decreases IP:IPR000971 IP:IPR000971 Protein 85a0a020-bc52-11e5-9b9d-001a4ae51247 PMC2916936 Another study showed that GATA-1 and Ikaros repress the gamma-globin gene during erythrogenesis when erythrocytes switch globin expression from the gamma to the beta gene, concurrent with conformational changes in the globin locus [13]. 1 MESH:D000096 activates IP:IPR000971 IP:IPR000971 Phenotype 51b4ea70-bc1e-11e5-8abe-001a4ae51246 10.1016/j.jchromb.2012.05.041 Degradation of the globin chains caused by acidified acetone might have been a possible reason.Fig. 1 CHEBI:66870 inhibits IP:IPR000971 IP:IPR000971 Chemical bcd8716a-bc36-11e5-ac4e-001a4ae51246 PMC3106018 However, under anaerobic conditions the globin was easily reduced by sodium dithionite or by NADPH under illumination with a 30 W deuterium lamp (Figure 2); the latter reaction being as fast as for human Ngb or Cyt-c while for Mb the reaction was an order of magnitude slower. 1 IP:IPR001519 inhibits IP:IPR000971 IP:IPR000971 ProteinFamily 4aa9122c-bc2a-11e5-8abe-001a4ae51246 10.1016/j.bbagen.2008.09.004 The same promoter region was recognized also by purified H-rich ferritin, and, more important, in a cellular model the expression of ferritin H-chain repressed the globin promoter, but not when the conserved region was mutated. 1 UNIPROT:P10242 decreases IP:IPR000971 IP:IPR000971 Protein d57fefce-c463-11e5-a92e-001a4ae51246 PMC3624254 "These results thus suggest that under normal differentiation conditions, MYB represses fetal globin gene expression by upregulating both the TR2/TR4 and KLF1/BCL11A pathways in human erythroid cells, but upon the downregulation of MYB, both the TR2/TR4 and KLF1/BCL11A pathways are suppressed, and this activates the fetal globin gene expression (Fig. 6G)." 1 UNIPROT:P10242 decreases IP:IPR000971 IP:IPR000971 Protein 5e715bfe-c47a-11e5-9cc6-001a4ae51246 PMC3029749 Concomitantly, we found that expression of the embryonic globin chain,ε-globin, was also dramatically increased by MYB knockdown (Fig. 3G). 1 CHEBI:30772 decreases IP:IPR000971 IP:IPR000971 Chemical 85fc40e4-3903-11e8-9192-001a4a160175 22705251 The specific histone deacetylase inhibitor butyric acid (BA) activates transcription of globin mRNA, leading to changes in cell morphology and induction to erythroid differentiation of erythroleukemic cell lines (Chénais et al., 1997; Weidner and Sommadossi, 1990; Safaya et al., 1994; Pace et al., 1994). 1 CHEBI:17968 inhibits IP:IPR000971 IP:IPR000971 Chemical 0d35c498-bbf9-11e5-9b9d-001a4ae51247 10.1016/j.bcmd.2010.10.013 Effect of p38 inhibitors on embryonic globin gene induction The loss of butyrate-mediated embryonic/fetal globin gene induction in the presence of p38 inhibitors, seen in K562 cells and CD34-derived erythroid precursor cells[6,19], was also present in FL EryD (Fig. 2A, representative experiment). 1 MESH:D051379 activates IP:IPR000971 IP:IPR000971 Phenotype c59c3092-cb28-11e5-8189-001a4ae51246 11743206 To allow the transfer of larger LCR and globin gene sequences, we proposed the use of RNA splicing and export controlling elements that include the Rev/R responsive element (RRE) components of human immunodeficiency virus (HIV) (21), and an RRE-bearing HIV-based lentiviral vector recently resulted in substantial amelioration of β-thalassemia in transplanted mice (22). 1 MESH:D051379 activates IP:IPR000971 IP:IPR000971 Phenotype a609d0c4-bbf4-11e5-9b9d-001a4ae51247 10.1016/j.exphem.2008.06.014 Targeted disruption of the ATF4 gene in mice produces a severe fetal anemia[132], while disruption of the GADD34 gene decreases the efficiency of globin mRNA translation[133]. 1 MESH:D051379 increases IP:IPR000971 IP:IPR000971 Phenotype 789a7160-c47e-11e5-9cc6-001a4ae51246 PMC2837319 These mice exhibit reduced globin gene transcription and die during transition from primitive to definitive hematopoiesis between E11.5 and E12.5.32Suppression of USF1 binding resulted in a significant decrease of PRMT1 recruitment and reduction in dimethyl H4R3 at LCR HS2 and the βmaj-promoter (Figure 1D-E). 1 MESH:D051379 decreases IP:IPR000971 IP:IPR000971 Phenotype 89e94154-c464-11e5-91a7-001a4ae51247 PMC3719677 Consequently,Klf1null mice have depleted levels of β-major globin and die at around E15 of severe anemia (43,44). 1 UNIPROT:P01375 decreases IP:IPR000971 IP:IPR000971 Protein 143a36b8-c467-11e5-a92e-001a4ae51246 24336657 Previous studies using this cell line have also demonstrated the TNF-α inhibition of globin expression and hemoglobin synthesis (32,35). 1 UNIPROT:P01579 decreases IP:IPR000971 IP:IPR000971 Protein 143a36b8-c467-11e5-a92e-001a4ae51246 24336657 In conclusion, IFN-γ suppresses activin A/NF-E2-induced globin expression through the NF-κB/c-Jun pathway. 1 UNIPROT:P02787 inhibits IP:IPR000971 IP:IPR000971 Protein d0769252-c46e-11e5-8491-001a4ae51247 PMC4023417 Transcriptional profiling in patient erythroblasts demonstrated downregulation of many mRNAs, includingHBB(a known KLF1 target) and B-cell lymphoma 11A (BCL11A), which encodes a TF that represses γ globin after birth.61-65Subsequent chromatin immunoprecipitation studies showed that wild-type KLF1 bindsBCL11Apromoter elements in adult, but not fetal liver erythroid progenitors.60Thus, KLF1 appears to mediate γ to β globin switching by binding theBCL11Agene and activating its transcription. 1 UNIPROT:P02787 increases IP:IPR000971 IP:IPR000971 Protein a1b657da-bbf5-11e5-8abe-001a4ae51246 PMC3779800 As there are numerous reports for the role of CDX4 in hematopoiesis (e.g.,Wang et al, 2005;Bansal et al, 2006;Lengerke et al, 2007), it is plausible that this TF directly regulates the expression of one or more globin genes, given their importance in red blood cell function. 1 MESH:D013577 inhibits IP:IPR000971 IP:IPR000971 Phenotype cd645424-c463-11e5-9cbe-001a4ae51247 PMC3552344 "THE THALASSEMIA SYNDROMES The thalassemia syndromes are inherited disorders characterized by absence or markedly decreased accumulation of one of the globin subunits of hemoglobin." 1 MESH:D013577 increases IP:IPR000971 IP:IPR000971 Phenotype 5a21e438-ca01-11e5-9b70-001a4ae51247 PMC4262245 "Perhaps due to the molecular and clinical diversity of the β thalassemia syndromes, and the need for therapeutics that are tolerable long-term, large collaborative trials of agents to reactivate fetal globin gene expression to high levels have not yet been undertaken in thalassemia, unlike sickle cell disease." 1 CHEBI:15430 activates IP:IPR000971 IP:IPR000971 Chemical 51d0c520-bc31-11e5-9b9d-001a4ae51247 10.1016/S0003-9861(03)00089-4 Mitochondrial Fe–protoporphyrin IX (heme) insertion into apo-globin chains occurs rapidly and promotes formation of stable globin chains in vitro[1]. 1 IP:IPR000971 increases IP:IPR000971 IP:IPR000971 ProteinFamily 18895864-c8ec-11e5-9faa-001a4ae51247 PMC2643510 While the human γ globin mRNA levels represent the majority of all β-like globin gene expression during late fetal life, the percentage of total mouse α-like globin to total β-like globin mRNA increases during this period as the γ globin genes switch to the nonfunctional human β0globin genes that have a relatively short-lived mRNA (supplemental Table S1, Part B). 1 IP:IPR000971 increases IP:IPR000971 IP:IPR000971 ProteinFamily 8af269a0-dc8d-11ea-a4b4-001a4a160175 PMC6123269 γ-to-β globin switching in neonatal period is driven by β-globin LCR, modulating β-like globin expressions by direct contact with their promoters. 1 IP:IPR000971 increases IP:IPR000971 IP:IPR000971 ProteinFamily 8486af26-3d13-11f0-afc2-0050569a791b PMC7483438 Along with limiting excess free heme, DBA erythroid cells also attempt to increase the level of globin chain translation by NRF2/Maf transcriptional activation of globin mRNA after BACH1 degradation and decreased EIF2α phosphorylation following inactivation and hypophosphorylation of HRI. 1 IP:IPR000971 decreases IP:IPR000971 IP:IPR000971 ProteinFamily 0d35c498-bbf9-11e5-9b9d-001a4ae51247 10.1016/j.bcmd.2010.10.013 We speculated that the loss of embryonic globin gene induction could be explained by an inhibitor-mediated disruption of ongoing erythropoiesis, whether mediated through p38 or through other, non-p38 cellular targets, rather than through inhibitionper seof p38-mediated induction of embryonic/fetal globin gene expression. 1 IP:IPR000971 inhibits IP:IPR000971 IP:IPR000971 ProteinFamily 03c49450-c8e9-11e5-a1fd-001a4ae51246 18258918 Heme also initiates globin transcription through inhibiting the DNA binding of the repressor, Bach1 (1), and globin translation through inhibiting substrate phosphorylation by the repressor, erythroid-specific eukaryotic initiation factor 2α kinase (2). 1 IP:IPR000971 increases IP:IPR000971 IP:IPR000971 ProteinFamily a3e37014-bbd8-11e5-8abe-001a4ae51246 PMC2228317 Multiple pathways control expression of the anoxia responsive globin genes Surprisingly, none of the HIF-1 responsive globin genes was induced whendaf-2(e1370)mutant animals were exposed to 12 h of oxygen deprivation (Table3). 1 IP:IPR000971 decreases IP:IPR000971 IP:IPR000971 ProteinFamily 55533c56-5c43-11e7-8e96-001a4ae51246 PMC5394953 Bach1 controls heme and globin balance by directly repressing its targets The balance of heme and globin levels is critical for proper erythroid development.4Therefore, we considered whether the globin gene expression might be altered inBach1−/−mice under LID-DW. 1 IP:IPR000971 increases IP:IPR000971 IP:IPR000971 ProteinFamily d06b7072-ae94-11ec-89b1-0050569a791b PMCPMC8158146 Sinceβ–thalassemia patients lack β–globin chains, one of the most frequent mechanisms for restoring optimal oxygen-carrying status is to induce γ–globin expression to regain the generation of HbF tetramers (α2γ2) [9]. 1 IP:IPR000971 decreases IP:IPR000971 IP:IPR000971 ProteinFamily 1061aa92-bbf9-11e5-8abe-001a4ae51246 10.1016/j.bcmd.2011.10.003 During embryonic and fetal stage KLF1 levels are low resulting in low levels of adult beta globin, while in the adult high KLF1 expression induces elevated levels of adult beta globin and BCL11A, which in turn represses gamma globin expression[4,8,9]. 1 IP:IPR000971 increases IP:IPR000971 IP:IPR000971 ProteinFamily c1af84ae-c473-11e5-9da3-001a4ae51247 PMC4475914 "The levels of these γ globin regulators have been previously demonstrated by others to modulate γ globin gene expression in either K562 cells or primary human erythroid cells (20–22,41)." 1 MESH:D006427 activates IP:IPR000971 IP:IPR000971 Phenotype 1d9e3598-d2df-11e5-888a-001a4ae51246 PMC345765 Addition of hemin to cultures with HMBA and dexamethasone initiated accumulation of globin mRNA but does not reverse the steroid-mediated inhibition of terminal cell division (that is, the cells retain their proliferative capacity). 1 MESH:D006427 inhibits IP:IPR000971 IP:IPR000971 Phenotype f956fd10-d75b-11e5-b317-001a4ae51247 PMC426749 1565-8The control of globin synthesis by hemin in cell-free preparations of rabbit reticulocytes is mediated by an inhibitor (translational repressor) of globin chain initiation that is inactivated by hemin. 1 GO:0034440 inhibits IP:IPR000971 IP:IPR000971 Phenotype d22d52a8-3405-11e8-9192-001a4a160175 28274434 Adduction of histidine residues in Mb by HNE likely increased Mb-mediated lipid oxidation by disrupting contacts between the heme moiety and neighboring amino acids of the globin. 1 MESH:D014233 activates IP:IPR000971 IP:IPR000971 Phenotype 9788c246-cb29-11e5-8189-001a4ae51246 PMC114998 "Furthermore, addition of the translation inhibitor aurin tricarboxylic acid, which has been shown to block all binding of globin mRNA to rabbit reticulocyte ribosomes (20-22,33), abolishes both globin and HCV 80S ribosome-protected peaks but allows the HCV 40S peak to persist (Fig.1G and H)." 1 UNIPROT:O75081 decreases IP:IPR000971 IP:IPR000971 Protein a45ee53e-bbf4-11e5-8abe-001a4ae51246 10.1016/j.exphem.2012.10.015 Overexpression of ETO2 significantly repressed globin expression (Figs.2,3). 1 UNIPROT:O75081 inhibits IP:IPR000971 IP:IPR000971 Protein a45ee53e-bbf4-11e5-8abe-001a4ae51246 10.1016/j.exphem.2012.10.015 These data suggest the ETO2 cooccupied with GATA-1 and SCL/TAL1 at the LCRs to repress globin genes. 1 UNIPROT:P49116 decreases IP:IPR000971 IP:IPR000971 Protein 88411170-c8e6-11e5-a1fd-001a4ae51246 PMC1864974 The data show that elevated TR2/TR4 expression reduced the peak level of ε‐globin transcription in the yolk sac and significantly accelerated ε transcriptional silencing. 1 UNIPROT:P49116 inhibits IP:IPR000971 IP:IPR000971 Protein a547d308-ee1b-11e5-872c-001a4ae51246 PMC4342359 In this way, by recruiting these interacting corepressors, TR2/TR4 elicits adult stage-specific silencing of the embryonic and fetal β-type globin genes. 1 UNIPROT:P49116 decreases IP:IPR000971 IP:IPR000971 Protein 09e6db50-bc3b-11e5-8abe-001a4ae51246 PMC3814094 The orphan receptors TR2 and TR4 are thought to suppress the expression of embryonic globin genes. 1 UNIPROT:Q96K83 decreases IP:IPR000971 IP:IPR000971 Protein 1ee2eef0-c8ec-11e5-b79b-001a4ae51246 19049973 Taken together with our results, it seems likely that the complex of GATA-1 and ZNF521 inhibits globin gene expression at an early stage of erythroid differentiation through complex formation with NuRD. 1 MESH:D006453 activates IP:IPR000971 IP:IPR000971 Phenotype c1af84ae-c473-11e5-9da3-001a4ae51247 PMC4475914 "A search for new γ globin-inducing agents for treating the hemoglobinopathies, including β-thalassemia major and SCD, is thus warranted." 1 UNIPROT:Q4FZB7 decreases IP:IPR000971 IP:IPR000971 Protein 760a38f6-c463-11e5-a92e-001a4ae51246 26802048 We also found that SUV4-20h1 repressed embryonic globin gene expression in mice, suggesting a conserved role for SUV4-20h1 during mammalian evolution. 1 MESH:D010146 inhibits IP:IPR000971 IP:IPR000971 Phenotype 139e3052-c484-11e5-91a7-001a4ae51247 PMC3496951 Discussion Previously identified risk factors for silent infarction in SCD include a lower pain event rate, history of seizures, increased leukocyte count, and Senegal ॆ globin haplotype27but not severe anemia. 1 FPLX:p38 increases IP:IPR000971 IP:IPR000971 ProteinFamily 0d35c498-bbf9-11e5-9b9d-001a4ae51247 10.1016/j.bcmd.2010.10.013 Any model of p38-mediated induction of embryonic/fetal globin gene expression would have to incorporate our observation that the highest levels of p38 phosphorylation in FL EryD is seen at harvest, when embryonic globin gene expression is low[30]. 1 PF:PF00668 activates IP:IPR000971 IP:IPR000971 ProteinFamily 65c834d2-bc4a-11e5-ac4e-001a4ae51246 10.1016/j.jobaz.2011.12.001 HbA1Cis produced by non-enzymatic condensation of glucose molecules with free amino acids on the globin component of hemoglobin (Beissuenger et al., 1993). 1 UNIPROT:P15976 increases IP:IPR000971 IP:IPR000971 Protein b6f88c60-c485-11e5-8491-001a4ae51247 PMC3510529 "GATA1 activates transcription of adult globin genes in erythroid cells of mice and humans by interacting with the zinc finger cofactor FOG1 to recruit the NuRD complex (8,9,22,30,31), which is mediated through its RbAp48 (RBBP4) subunit (7,30)." 1 UNIPROT:P15976 activates IP:IPR000971 IP:IPR000971 Protein b3a66e14-c8eb-11e5-a801-001a4ae51246 18767169 GATA-1 can both activate and repress globin genes, but the study of this factor is complicated because of its involvement in activation and repression of many transcription factors involved in erythroid differentiation. 1 UNIPROT:P15976 methylatesProtein IP:IPR000971 IP:IPR000971 Protein d90bcbb6-3797-11e6-b56c-001a4ae51246 PMC4818787 These transcription factors alter globin gene expression by affecting the promoter regions as well as locus control region (LCR).13It has been shown that GATA-1 augments gene expression by means of increasing H3K4di- and trimethylation of β – globin gene. 1 UNIPROT:P15976 increases IP:IPR000971 IP:IPR000971 Protein 3b73b586-c8ec-11e5-8b47-001a4ae51246 PMC2648246 "Among these, GATA-1 and its cofactor FOG-1 (for Friend of GATA-1) (52), EKLF (9), and NLI/Lbd1 (46) are required for efficient long-range chromatin interactions between βLCR and β-like globin genes, thereby promoting high-level globin gene expression." 1 UNIPROT:P26358 increases IP:IPR000971 IP:IPR000971 Protein a547d308-ee1b-11e5-872c-001a4ae51246 PMC4342359 Loss of LSD1 and DNMT1 alter erythropoiesis, globin transcription, and corepressor binding on globin gene promoters Previously, we found that TR2/TR4 physically interacts with LSD1 and DNMT1 to form a core tetrameric repressor complex.28This core complex then (presumably) assumes additional functions as it can independently associate with other coeffector proteins to form even larger complexes.28To understand the role of each component within the core complex, we examined the effects ofLsd1orDnmt1genetic loss of function on β-type globin gene transcription and erythropoiesis using the same experimental system. 1 UNIPROT:Q968Y9 increases IP:IPR000971 IP:IPR000971 Protein a3e37014-bbd8-11e5-8abe-001a4ae51246 PMC2228317 This could indicate that HIF-1 mediates induction of these genes upon anoxia treatment and that HIF-1 activity is modulated by insulin/IGF-1 signaling, or that HIF-1 and DAF-2 each act to regulate the expression of these globin genes. 1 UNIPROT:Q92785 activates IP:IPR000971 IP:IPR000971 Protein b0d90220-bc19-11e5-8abe-001a4ae51246 PMC4066795 Several points should be emphasized from the perspective of REQ-mediated globin-switching. 1 UNIPROT:Q9BQI3 inhibits IP:IPR000971 IP:IPR000971 Protein 92e9fe88-bc03-11e5-9b9d-001a4ae51247 10.1016/j.fct.2013.10.017 Hri is activated in both cases to prevent excess globin translation through general inhibition by phosphorylation of α-subunit of the eukaryotic translation initiation factor 2. 1 UNIPROT:Q9BQI3 inhibits IP:IPR000971 IP:IPR000971 Protein 89c56048-c46b-11e5-85e4-001a4ae51246 PMC4300761 "HRI is activated by heme deficiency to prevent the synthesis of globin peptides in response to elevated heme levels." 1 UNIPROT:Q9BQI3 increases IP:IPR000971 IP:IPR000971 Protein 3009809a-c8ec-11e5-878b-001a4ae51247 PMC2652363 Bach I is a nuclear repressor that inhibits both α and β globin gene transcription when heme concentration is low.71-73Heme regulated inhibitor of translation (HRI) is a cytosolic heme-binding protein that represses globin translation in erythroid precursors during heme deficiency.74 HRI is a member of a small family of protein kinases that inhibit translation by phosphorylating the α subunit of eukaryotic translational initiation factor 2 (eIF2α). 1 UNIPROT:Q9BQI3 decreases IP:IPR000971 IP:IPR000971 Protein 3009809a-c8ec-11e5-878b-001a4ae51247 PMC2652363 Bach I is a nuclear repressor that inhibits both α and β globin gene transcription when heme concentration is low.71-73Heme regulated inhibitor of translation (HRI) is a cytosolic heme-binding protein that represses globin translation in erythroid precursors during heme deficiency.74 HRI is a member of a small family of protein kinases that inhibit translation by phosphorylating the α subunit of eukaryotic translational initiation factor 2 (eIF2α). 1 UNIPROT:Q9BQI3 activates IP:IPR000971 IP:IPR000971 Protein 159385ee-bc4e-11e5-8d2d-001a4ae51247 PMC3962220 Hemoglobin consists of heme and globin, and when production of globin exceeds that of heme, HRI is activated and suppresses globin synthesis in erythrocytes by phosphorylating eIF2α. 1 UNIPROT:Q9BQI3 inhibits IP:IPR000971 IP:IPR000971 Protein 8863ad52-3531-11e8-8f56-001a4a160175 24560123 In addition to this chaperone role of AHSP, HRI also protects erythroblasts from excess α-globin or β-globin chain accumulations, as occurs in thalassemia, because the attendant oxidant stress from the denatured globin chains induces HRI, which inhibits further globin mRNA translation[85]. 1 UNIPROT:Q9BQI3 activates IP:IPR000971 IP:IPR000971 Protein ff0d02c2-8cc0-11ee-add2-0050569a791b 10.1007/s12032-022-01668-1 As stated above, HRI is abundantly expressed in erythroid cells and becomes activated in the absence of heme, preventing the accumulation of inactive (misfolded) globin with no heme co-factor [27]; however, recent studies indicated that HRI is ubiquitously expressed and induces eIF2α phosphorylation in various cell types in response to several different stressors (e.g., sodium arsenite, oxidative stress, osmotic stress, heat shock, and proteasomal inhibition) [28,29,30–31]. 1 UNIPROT:Q9BQI3 activates IP:IPR000971 IP:IPR000971 Protein 107f4e64-ea1f-11ee-8b99-0050569a1f61 PMC9520036 HRI functions as a heme sensor, modulating globin synthesis with the amount of heme available for hemoglobin production (1, 6, 8). 1 CHEBI:49709 activates IP:IPR000971 IP:IPR000971 Chemical 8d9cf260-3518-11e8-9192-001a4a160175 22579021 Methemoglobin formed a destabilizing complex with chlorate, which caused denaturation of globin, cross-linking of erythrocyte membrane proteins, increased red blood cell membrane rigidity, and inactivation of membrane enzymes, reducing the erythrocytes’ ability to cope with oxidative stress and hence, resulting in autocatalytic formation of further methemoglobin and accelerated erythrocyte destruction in a “vicious circle”(6,7). 1 CHEBI:5032 activates IP:IPR000971 IP:IPR000971 Chemical 230d6a86-bc4f-11e5-9b9d-001a4ae51247 10.1016/S0309-1740(00)00121-2 Hegesh and Avron (1967)hypothesised that ferrocyanide induces a change in the globin structure by binding to the heam protein. 1 CHEBI:16474 inhibits IP:IPR000971 IP:IPR000971 Chemical bcd8716a-bc36-11e5-ac4e-001a4ae51246 PMC3106018 However, under anaerobic conditions the globin was easily reduced by sodium dithionite or by NADPH under illumination with a 30 W deuterium lamp (Figure 2); the latter reaction being as fast as for human Ngb or Cyt-c while for Mb the reaction was an order of magnitude slower. 1 MESH:D012333 activates IP:IPR000971 IP:IPR000971 Phenotype 9e0a9d4e-d6cb-11e5-81c0-001a4ae51246 PMC388182 Appropriate control experiments indicate that the virus-associated globin messenger RNA is resistant to degradation by exogenous ribonuclease; that exogenously added globin messenger RNA does not become associated with the 60S viral RNA complex; and that globin messenger RNA can be detected in virions derived from cells both induced for and constitutively synthesizing globin messenger RNA. 1 FPLX:Hemoglobin decreases IP:IPR000971 IP:IPR000971 ProteinFamily 97c231b2-3524-11e9-ab56-001a4a160175 PMC6024639 In hereditary persistence of fetal hemoglobin (HPFH), a benign genetic condition, mutations attenuate γ-to-β globin switching, causing high fetal globin (HbF) levels throughout life, thus alleviating the clinical manifestations of these disorders.4This provided a rationale for gene therapy approaches of hemoglobinopathies aimed toward the reversal of globin switching (reviewed by Vinjamur et al5and Psatha et al6). 1 FPLX:Hemoglobin activates IP:IPR000971 IP:IPR000971 ProteinFamily 84b371bb-f597-11eb-9804-001a4a160176 31042626 We also speculated that the acceleration effect observed in the present study was due to some change in the globin protein moiety induced by photochemical sensitization of Fe(II) hemoglobin (Fig. 6). 1 FPLX:Hemoglobin inhibits IP:IPR000971 IP:IPR000971 ProteinFamily 78d66120-bc40-11e5-8abe-001a4ae51246 PMC3917141 In solution, fetal hemoglobin concentration higher than 15% prevents sickle globin polymerization35. 1 FPLX:Hemoglobin activates IP:IPR000971 IP:IPR000971 ProteinFamily 447aec0e-bc43-11e5-ac4e-001a4ae51246 PMC3560109 However, the high concentration of hemoglobin transcripts in peripheral blood can induce a globin interference effect, effectively reducing a microarray’s detection sensitivity and increasing its signal variability [17]. 1 MESH:D001374 activates IP:IPR000971 IP:IPR000971 Phenotype 75c48052-d1df-11e5-aade-001a4ae51247 PMC345346 U.S.A.Activation of a chicken embryonic globin gene in adult erythroid cells by 5-azacytidine and sodium butyrate. 1 MESH:D001374 decreases IP:IPR000971 IP:IPR000971 Phenotype ac95e74c-c46f-11e5-85e4-001a4ae51246 PMC4187729 "The DNMT inhibitors 5-azacytidine and 5-aza-2′-deoxycytidine (decitabine) have been shown to lead to demethylation of the fetal globin gene promoters and to induce fetal globin gene expression (114–117); decitabine, in particular, is currently in clinical trials and is being tested as a possible therapeutic human γ-globin inducer." 1 MESH:D001374 increases IP:IPR000971 IP:IPR000971 Phenotype 3ab66510-375a-11e8-8f56-001a4a160175 PMC6438182 Early studies showed that 5-azacytidine could restore expression of fetal and embryonic globin genes in animal models and increase HbF in adult baboons and humans, implicating DNA methylation in globin gene silencing (Charache et al., 1983; DeSimone et al., 1982; Ginder et al., 1984; Ley et al., 1982). 1 UNIPROT:P61006 activates IP:IPR000971 IP:IPR000971 Protein 332ad350-c8e7-11e5-9624-001a4ae51246 17855381 Induction of MEL and K562 cells by DMSO or HMBA is known to induce globin synthesis and production of erythroid-specific markers (for reviews, seeMarks and Rifkind, 1978;Koeffler and Golde, 1980). 1 UNIPROT:Q5VYS8 increases IP:IPR000971 IP:IPR000971 Protein d9bbe202-bc19-11e5-8abe-001a4ae51246 PMC2760785 For instance, HS2 alone can enhance globin gene expression in EryC, although it does not protect transgenes from position effects (39). 1 UNIPROT:Q5VYS8 activates IP:IPR000971 IP:IPR000971 Protein 88f87996-c477-11e5-85e4-001a4ae51246 PMC4579329 "ZFs designed to artificially coordinate genomic looping between the HS2 enhancer of the globin locus control region and the beta-globin promoter activate gene expression in mouse cells (Deng et al. 2012) and similar designs can direct differential gene expression patterns between HS2 and globin genes in human and mouse cell lines (Deng et al. 2014)." 1 UNIPROT:Q5VYS8 activates IP:IPR000971 IP:IPR000971 Protein 471c2a5c-c479-11e5-8491-001a4ae51247 PMC3261562 The human tDNA‐containing fragments were cloned between the murine HS2 enhancer of the globin locus and a neomycin reporter driven by the human γ‐globin promoter. 1 UNIPROT:Q5VYS8 increases IP:IPR000971 IP:IPR000971 Protein fc3f805e-bc19-11e5-8abe-001a4ae51246 PMC2018613 While HS sites 1, 3, 4 and 5 possess weak or no enhancer activity, the HS2 site, located respectively 11 and 55 kb upstream of the ε- and β-globin genes, possesses prominent enhancer activity (13–15) and is able to activate transcription of the globin genes over the long distance (16). 1 FPLX:FGF decreases IP:IPR000971 IP:IPR000971 ProteinFamily b9518ed0-bc47-11e5-9b9d-001a4ae51247 PMC4050694 Also, elevated levels of FGF enhanced the expression of PGCs, and downregulated the expression of globin, the latter resembling the effects of FGF in Xenopus (Isaacs et al., 2007; Walmsley et al., 2008). 1 UNIPROT:P04070 activates IP:IPR000971 IP:IPR000971 Protein 820c6cc4-3c8a-11f0-afc2-0050569a791b PMC9260135 "10.1534/genetics.107.072553, 17435244, PMC1894593 Sawado 2001 Sawado T. Igarashi K. Groudine M. Activation of β-major globin gene transcription is associated with recruitment of NF-E2 to the β-globin LCR and gene promoter Proc." 1 CHEBI:39867 increases IP:IPR000971 IP:IPR000971 Chemical fde32d36-bc26-11e5-8abe-001a4ae51246 10.1016/j.mehy.2006.10.032 Researchers investigated the activity of valproic acid in human erythroid cell cultures and showed that valproic acid alone or in combination with hemin accelerated fetal globin expression in cultures of erythroid progenitors derived from normal adults, compound heterozygotes for β-thalassemia and sickle cell anemia and in cord blood samples[2]. 1 UNIPROT:P00390 inhibits IP:IPR000971 IP:IPR000971 Protein 4966b0b8-c8e6-11e5-9ad8-001a4ae51247 17971501 The contribution of the first eigengene was almost twice that of the second eigengene and was strongly associated with globin genes, as shown inTable 2B; 57, 43, and 43% hemoglobin genes were ranked as top gene expression values for T7, T7+GR, and NuGEN, respectively, all withP< 0.0001 which were calculated by hypergeometric statistics.Figure 3Bindicates that, despite attempts at globin reduction by the T7+GR protocol, expression of globin gene values ranked highest across the entire 54,000-probe set for all three protocols. 1 UNIPROT:P51532 increases IP:IPR000971 IP:IPR000971 Protein f038a164-bc19-11e5-9b9d-001a4ae51247 PMC2764439 RESULTS results BRG1 directly regulates α globin expression We previously identified reduced transcription of the α and β globin genes in flow-sorted erythroid cells from E12.5Brg1null/ENU1fetal livers (FLs) (12,27,28). 1 UNIPROT:P51532 increases IP:IPR000971 IP:IPR000971 Protein cfc5c4b8-c464-11e5-85e4-001a4ae51246 PMC3767509 BRG1 promotes expression of adult α- and β-like globin genes in erythroid cells (19,24), CBP/p300 mediates GATA-1 function in at least certain contexts (21), and Med1 amplifies GATA-1 activity at select target genes (22). 1 UNIPROT:Q86X55 decreases IP:IPR000971 IP:IPR000971 Protein 5abdcbfa-c490-11e8-9c11-001a4a160175 30257864 "CARM1 represses globin gene expression through methylation of PRMT5 To examine whether Arg-505 in PRMT5 is asymmetrically dimethylated, we used the peptide MPYVVR (me2a) LHNFH, which corresponds to amino acids 500–510 of the human PRMT5 protein, where arginine is asymmetrically demethylated, as an antigen to generate a rabbit polyclonal antibody." 1 UNIPROT:P35712 decreases IP:IPR000971 IP:IPR000971 Protein ddd99b7a-c8eb-11e5-a4c6-001a4ae51246 PMC2573226 Sox6 promotes chondrogenesis (73), represses embryonic β-like globin transcription in definitive erythroid cells (91), and functions cell autonomously to promote proliferation, survival, and differentiation of erythroid cells (18). 1 UNIPROT:O95600 inhibits IP:IPR000971 IP:IPR000971 Protein 25732326-bc2a-11e5-8abe-001a4ae51246 PMC4011606 For example, KLF8 can negatively regulate the globin and E-cadherin genes through contact with the C-terminal Binding Protein (CtBP) corepressor. 1 UNIPROT:P01106 activates IP:IPR000971 IP:IPR000971 Protein 33bd42b2-bc35-11e5-8d2d-001a4ae51247 PMC4315404 On the other hand, globin γ was markedly decreased in c-Myc overexpressing cells (lane 3 and 6), while knocking down c-Myc increased globin γ protein level (lane 1 and 2), which was further enhanced by combination of c-Myc shRNA and NC treatment (lane 5). 1 UNIPROT:Q9NZD4 inhibits IP:IPR000971 IP:IPR000971 Protein c9e202aa-3532-11e8-8f56-001a4a160175 24188961 In addition to this, several recent studies showed that α-hemoglobin stabilizing protein (AHSP) could prevent α globin precipitation and hereby have a positive effect on hemoglobin production (Feng et al., 2004; Feng et al., 2005; Vasseur-Godbillon et al., 2006). 1 UNIPROT:Q9NZD4 activates IP:IPR000971 IP:IPR000971 Protein 11a4e13e-c8de-11e5-a1fd-001a4ae51246 16901899 The initial binding of AHSP to free oxy-αHb causes disordering of the globin F helix, movement of the heme group, displacement of the F8 histidine, coordination of the Fe(II) heme iron by the distal histidine (E7), and binding of O2to the proximal side of the heme group (5). 1 UNIPROT:Q9NZD4 inhibits IP:IPR000971 IP:IPR000971 Protein 266bcfb8-c471-11e5-a92e-001a4ae51246 PMC2700329 In human K562 erythroleukemia cells, AHSP deficiency induces α globin precipitation and apoptosis. 1 UNIPROT:Q99578 inhibits IP:IPR000971 IP:IPR000971 Protein 66511bea-5c20-11e7-af4d-001a4ae51247 PMC5385538 Genes that responded to PRRSV infection at any of the days after infection compared to the day 0 baseline were determined in edgeR using a generalized linear model that took the following factors into account: day, gender, trial (PHGC3 versus PHGC5), post globin depletion RIN score, and population structure (covariates for the first three PCAs based on the SNP genotypes of the 44 animals). 1 PUBCHEM:6804 activates IP:IPR000971 IP:IPR000971 Chemical 78f950a6-bc2a-11e5-8abe-001a4ae51246 PMC4005505 There is also evidence that HU can act as a nitric oxide donor and increase cyclic guanosine monophosphate (cGMP) levels, which upregulate the translation of the γ globin. 1 MESH:D004791 activates IP:IPR000971 IP:IPR000971 Phenotype e75ad454-8270-11e6-81bd-001a4ae51246 PMC5027816 Hydroxyurea has also been used as an effective treatment modality for EMH.13This ribonucleotide reductase enzyme inhibitor reduces the globin chain imbalance through stimulation of fetal hemoglobin synthesis, thereby ameliorating ineffective erythropoiesis, which is the primary stimulus for EMH development progression. 1 MESH:D000077209 increases IP:IPR000971 IP:IPR000971 Phenotype ac95e74c-c46f-11e5-85e4-001a4ae51246 PMC4187729 "The DNMT inhibitors 5-azacytidine and 5-aza-2′-deoxycytidine (decitabine) have been shown to lead to demethylation of the fetal globin gene promoters and to induce fetal globin gene expression (114–117); decitabine, in particular, is currently in clinical trials and is being tested as a possible therapeutic human γ-globin inducer." 1 UNIPROT:P23769 activates IP:IPR000971 IP:IPR000971 Protein e01b4022-c478-11e5-91a7-001a4ae51247 PMC3138678 In committed, undifferentiated red blood cells, GATA-2 binds to the β-globin locus and activates low-level expression of the appropriate globin gene. 1 UNIPROT:O95684 activates IP:IPR000971 IP:IPR000971 Protein cd804f3e-c47d-11e5-91a7-001a4ae51247 PMC2993632 In contrast, expression of SOX6 is reduced, indicating that depletion of FOP might modulate SOX6-dependent silencing of γ globin in adult HEP cells. 1 CHEBI:87986 decreases IP:IPR000971 IP:IPR000971 Chemical a7e84766-bc3c-11e5-8d2d-001a4ae51247 PMC3131236 H3K27me3 at the α globin genes occurs at high levels in ES cells and decreases during erythroid differentiation We have previously shown that α globin expression is repressed in non-erythroid cells by PcG and its associated silencing mark H3K27me3. 1 CHEBI:87986 inhibits IP:IPR000971 IP:IPR000971 Chemical a7e84766-bc3c-11e5-8d2d-001a4ae51247 PMC3131236 It appears that, rather than carrying a preimposed bivalent epigenetic signature which silences them, in pluripotent ES cells the α globin genes are repressed by PcG and comodified at readily detectable levels by H3K4me3 when expressed, even at basal levels. 1 CHEBI:3330 decreases IP:IPR000971 IP:IPR000971 Chemical 605a06f8-c472-11e5-9da3-001a4ae51247 PMC2740439 We show here that another such inhibitor, calpeptin, inhibited m-calpain and induced expression of the adult globin genes. 1 CHEBI:30768 increases IP:IPR000971 IP:IPR000971 Chemical 12b886a0-cc8c-11e5-888a-001a4ae51246 PMC20860 "Recently, butyrate and its metabolic derivatives phenylbutyrate and phenylacetate have been used in clinical trials to increase fetal hemoglobin (HbF) expression in patients with thalassemia or sickle cell disease (34–38), and the short chain fatty acid propionic acid has also been reported to stimulate fetal globin gene expression (39)." 1 CHEBI:30768 increases IP:IPR000971 IP:IPR000971 Chemical 44f4b242-c471-11e5-a92e-001a4ae51246 PMC2710936 We found that the concentrations of propionic acid achieved in the PCCA KO strain in vivo were not able to activate embryonic globin gene expression in murine EryD in vitro. 1 CHEBI:34544 inhibits IP:IPR000971 IP:IPR000971 Chemical 9788c246-cb29-11e5-8189-001a4ae51246 PMC114998 "Furthermore, addition of the translation inhibitor aurin tricarboxylic acid, which has been shown to block all binding of globin mRNA to rabbit reticulocyte ribosomes (20-22,33), abolishes both globin and HCV 80S ribosome-protected peaks but allows the HCV 40S peak to persist (Fig.1G and H)." 1 UNIPROT:Q9NX58 decreases IP:IPR000971 IP:IPR000971 Protein acba28c2-bc19-11e5-8abe-001a4ae51246 PMC4150809 LYAR represses γ−globin gene expression in K562 cells To determine the role of LYAR in γ-globin gene regulation, we generated two stable LYAR knockdown K562 cell lines using lentiviral vectors containing specific shRNAs. 1 UNIPROT:Q16621 increases IP:IPR000971 IP:IPR000971 Protein 9d7ee13e-ca5d-11e5-a3f7-001a4ae51246 12509425 There appears to be considerable functional redundancy among polypeptides that recognize NF-E2 sites, and whereas the p18–p45 NF-E2 dimer itself may be required to activate globin gene expression, other species may be able to participate in the formation of the HSs (13).