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Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6
Open accessAbstract
The developmental switch from human fetal (γ) to adult (β) hemoglobin represents a clinically important example of developmental gene regulation. The transcription factor BCL11A is a central mediator of γ-globin silencing and hemoglobin switching. Here we determine chromatin occupancy of BCL11A at the human β-globin locus and other genomic regions in vivo by high-resolution chromatin immunoprecipitation (ChIP)–chip analysis. BCL11A binds the upstream locus control region (LCR), ɛ-globin, and the intergenic regions between γ-globin and δ-globin genes. A chromosome conformation capture (3C) assay shows that BCL11A reconfigures the β-globin cluster by modulating chromosomal loop formation. We also show that BCL11A and the HMG-box-containing transcription factor SOX6 interact physically and functionally during erythroid maturation. BCL11A and SOX6 co-occupy the human β-globin cluster along with GATA1, and cooperate in silencing γ-globin transcription in adult human erythroid progenitors. These findings collectively demonstrate that transcriptional silencing of γ-globin genes by BCL11A involves long-range interactions and cooperation with SOX6. Our findings provide insight into the mechanism of BCL11A action and new clues for the developmental gene regulatory programs that function at the β-globin locus.
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“Subsequent studies demonstrated that BCL11A, a zinc- fi nger transcription factor, is a bona fi de repressor of HbF expression (4 -7).”
From Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A (2013) · cites this paper as [6]
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“Further molecular studies revealed that BCL11A interacts with several erythroid regulators including GATA1, FOG1, and SOX6, and with the nucleosome remodeling and deacetylase complex (NuRD) (4, 6).”
From Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A (2013) · cites this paper as [6]
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“In control cells, ChIP analysis revealed that BCL11A occupies several discrete regions within the human β -globin cluster, including the DNase I hypersensitive site 3 (HS3) within the locus control region (LCR), the e -globin promoter, and the γδ -intergenic region, consistent with previous analyses (4, 6).”
From Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A (2013) · cites this paper as [6]
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Metadata
- Authors
- Xu, J., Sankaran, V. G., Ni, M., Menne, T. F., Puram, R. V., Kim, W., & Orkin, S. H.
- Affiliations
- Boston Children's Hospital (US)
- Harvard University (US)
- Harvard–MIT Division of Health Sciences and Technology (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2010-04-15
- Volume
- 24
- Issue
- 8
- Pages
- 783-798
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2854393
- OpenAlex
- W2134881764
- Semantic Scholar
- 097ee5589990708503598c372d66d87bf5262280
- Cited by
- 361
- References
- 71
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 19 · 2023: 15 · 2022: 23 · 2021: 21 · 2020: 20 · 2019: 17 · 2018: 21 · 2017: 31 · 2016: 30 · 2015: 25 · 2014: 26 · 2013: 23 · 2012: 22
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Kay Kendall Leukaemia Fund
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL032259, T32HL116324)
- National Cancer Institute (K12CA087723)
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Health Sciences › Medicine › Genetics (clinical) › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Keywords
- BCL11A, SOX6, beta-globin locus, hemoglobin switching, long-range chromatin interactions, chromatin looping, locus control region, erythroid maturation, GATA-1, erythroid progenitor cells, developmental gene regulation, chromatin occupancy
- MeSH terms
- Adult, Animals, Carrier Proteins, Cell Line, Erythropoiesis, Histones, Humans, Nuclear Proteins, Protein Binding, Repressor Proteins, Gene Expression Regulation, Developmental, Gene Silencing, Protein Transport, Erythroid Cells, GATA1 Transcription Factor, Mice, gamma-Globins, SOXD Transcription Factors
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