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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BCL11A is a bona fide repressor of HbF expression.
“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]
BCL11A interacts with GATA1, FOG1, SOX6, and the NuRD complex.
“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]
In control cells, BCL11A occupies HS3 within the LCR, the ε-globin promoter, and the γδ-intergenic region.
“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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- 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 › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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