Cited by 361Hemoglobinopathies and Related DisordersGenomics and Chromatin DynamicsHemoglobin structure and function

Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6

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Xu, Jian, Sankaran, Vijay G., Ni, Min, Menne, Tobias F., Puram, Rishi V., Kim, Woojin, Orkin, Stuart H.·2010·Genes & Development

Abstract

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).”
  • 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).”
  • 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).”

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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
Published
2010-04-15
Volume
24
Issue
8
Pages
783-798
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
OpenAlex
W2134881764
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
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

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