Mi2β Is Required for γ-Globin Gene Silencing: Temporal Assembly of a GATA-1-FOG-1-Mi2 Repressor Complex in β-YAC Transgenic Mice

Costa, Flavia C; Fedosyuk, Halyna; Chazelle, Allen; Neades, Renee; Peterson, Kenneth R.

doi:10.1371/journal.pgen.1003155

Cited by 29 publications

(41 citation statements)

References 43 publications

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“…S3). Consistent with a role in HbF silencing, knockdown or KO of Mi-2β reactivates γ-globin genes in the β-YAC transgenic mice (23,24). However, the degree of γ-globin induction is substantially less than that seen with BCL11A deficiency (8).…”

Section: Discussionmentioning

confidence: 63%

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

Bauer

Kerényi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

197

188

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Reactivation of fetal hemoglobin (HbF) in adults ameliorates the severity of the common β-globin disorders. The transcription factor BCL11A is a critical modulator of hemoglobin switching and HbF silencing, yet the molecular mechanism through which BCL11A coordinates the developmental switch is incompletely understood. Particularly, the identities of BCL11A cooperating protein complexes and their roles in HbF expression and erythroid development remain largely unknown. Here we determine the interacting partner proteins of BCL11A in erythroid cells by a proteomic screen. BCL11A is found within multiprotein complexes consisting of erythroid transcription factors, transcriptional corepressors, and chromatinmodifying enzymes. We show that the lysine-specific demethylase 1 and repressor element-1 silencing transcription factor corepressor 1 (LSD1/CoREST) histone demethylase complex interacts with BCL11A and is required for full developmental silencing of mouse embryonic β-like globin genes and human γ-globin genes in adult erythroid cells in vivo. In addition, LSD1 is essential for normal erythroid development. Furthermore, the DNA methyltransferase 1 (DNMT1) is identified as a BCL11A-associated protein in the proteomic screen. DNMT1 is required to maintain HbF silencing in primary human adult erythroid cells. DNMT1 haploinsufficiency combined with BCL11A deficiency further enhances γ-globin expression in adult animals. Our findings provide important insights into the mechanistic roles of BCL11A in HbF silencing and clues for therapeutic targeting of BCL11A in β-hemoglobinopathies.gene regulation | globin switching | hematopoiesis

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Section: Discussionmentioning

confidence: 63%

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

Bauer

Kerényi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

197

188

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“…The A ␥-globin gene is silenced during development following sequential binding of GATA-1, friend of GATA-1 (FOG-1), and Mi2␤ proteins at the Ϫ566 GATA site relative to the A ␥-globin gene cap site in the fetal liver between postconception days 16 and 18 (E16 and E18) (10,11). GATA-1 is the DNA binding moiety in this complex, but GATA-1 can recruit both coactivators and corepressors in both FOG-1-dependent and -independent pathways (12)(13)(14)(15).…”

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confidence: 99%

O-Linked N-Acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Interact with Mi2β Protein at the Aγ-Globin Promoter

Zhang

Costa²,

Tan

et al. 2016

Journal of Biological Chemistry

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One mode of ␥-globin gene silencing involves a GATA-1⅐FOG-1⅐Mi2␤ repressor complex that binds to the ؊566 GATA site relative to the A ␥-globin gene cap site. However, the mechanism of how this repressor complex is assembled at the ؊566 GATA site is unknown. In this study, we demonstrate that the O-linked N-acetylglucosamine (O-GlcNAc) processing enzymes, O-GlcNAc-transferase (OGT) and O-GlcNAcase (OGA), interact with the A ␥-globin promoter at the ؊566 GATA repressor site; however, mutation of the GATA site to GAGA significantly reduces OGT and OGA promoter interactions in ␤-globin locus yeast artificial chromosome (␤-YAC) bone marrow cells. When WT ␤-YAC bone marrow cells are treated with the OGA inhibitor Thiamet-G, the occupancy of OGT, OGA, and Mi2␤ at the A ␥-globin promoter is increased. In addition, OGT and Mi2␤ recruitment is increased at the A ␥-globin promoter when ␥-globin becomes repressed in postconception day E18 human ␤-YAC transgenic mouse fetal liver. Furthermore, we show that Mi2␤ is modified with O-GlcNAc, and both OGT and OGA interact with Mi2␤, GATA-1, and FOG-1. Taken together, our data suggest that O-GlcNAcylation is a novel mechanism of ␥-globin gene regulation mediated by modulating the assembly of the GATA-1⅐FOG-1⅐Mi2␤ repressor complex at the ؊566 GATA motif within the promoter.

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“…This polymorphism disrupted a GATA-binding motif in the G ␥ globin far upstream promoter that was also duplicated in the A ␥ globin (HBG1) gene (located 566 bp 5= to the A ␥ start site) (102). Disruption of the Ϫ566 A ␥ GATA site in ␤-globin YAC mutant mice resulted in persistent expression of the A ␥ gene in adult mice (103). These studies suggest a contribution of a GATA transcription factor(s) to fetal globin silencing.…”

Section: Gata1 and Klfs: Erythroid Regulatory Proteins That Influencementioning

confidence: 99%

Fetal Globin Gene Repressors as Drug Targets for Molecular Therapies To Treat the β-Globinopathies

Suzuki

Yamamoto

Engel

2014

Molecular and Cellular Biology

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The human ␤-globin locus is comprised of embryonic, fetal, and adult globin genes that are expressed in a developmental stagespecific manner. Mutations in the globin locus give rise to the ␤-globinopathies, ␤-thalassemia and sickle cell disease, which begin to manifest symptoms around the time of birth. Although the fetal globin genes are autonomously silenced in adult-stage erythroid cells, mutations lying both within and outside the locus lead to natural variations in the level of fetal globin gene expression, and some of these significantly ameliorate the clinical symptoms of the ␤-globinopathies. Multiple reports have now identified several transcription factors that are involved in fetal globin gene repression in definitive (adult)-stage erythroid cells (the TR2/TR4 heterodimer, MYB, KLFs, BCL11A, and SOX6). To carry out their repression functions, chromatin-modifying enzymes (such as DNA methyltransferase, histone deacetylases, and lysine-specific histone demethylase 1) are additionally involved as a consequence of forming large macromolecular complexes with the DNA-binding subunits of these cellular machines. This review focuses on the molecular mechanisms underlying fetal globin gene silencing and possible near-future molecularly targeted therapies for treating the ␤-globinopathies.

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Mi2β Is Required for γ-Globin Gene Silencing: Temporal Assembly of a GATA-1-FOG-1-Mi2 Repressor Complex in β-YAC Transgenic Mice

Cited by 29 publications

References 43 publications

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

O-Linked N-Acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Interact with Mi2β Protein at the Aγ-Globin Promoter

Fetal Globin Gene Repressors as Drug Targets for Molecular Therapies To Treat the β-Globinopathies

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