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PMID: 20395365 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Transcriptional silencing of {gamma}-globin by BCL11A involves long-range interactions and cooperation with SOX6.

Genes & development ·Vol. 24 ·No. 8 ·2010-04-15 ·Pages 783-98

Xu J, Sankaran VG, Ni M, Menne TF, Puram RV, Kim W, Orkin SH

Abstract

The developmental switch from human fetal (gamma) to adult (beta) hemoglobin represents a clinically important example of developmental gene regulation. The transcription factor BCL11A is a central mediator of gamma-globin silencing and hemoglobin switching. Here we determine chromatin occupancy of BCL11A at the human beta-globin locus and other genomic regions in vivo by high-resolution chromatin immunoprecipitation (ChIP)-chip analysis. BCL11A binds the upstream locus control region (LCR), epsilon-globin, and the intergenic regions between gamma-globin and delta-globin genes. A chromosome conformation capture (3C) assay shows that BCL11A reconfigures the beta-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 beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. These findings collectively demonstrate that transcriptional silencing of gamma-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 beta-globin locus.

MeSH Terms
Adult Animals Carrier Proteins/metabolism Cell Line Erythroid Cells/cytology,metabolism Erythropoiesis/physiology GATA1 Transcription Factor/metabolism Gene Expression Regulation, Developmental Gene Silencing Histones/metabolism Humans Mice Nuclear Proteins/metabolism Protein Binding Protein Transport Repressor Proteins SOXD Transcription Factors/metabolism gamma-Globins/metabolism
Chemicals
BCL11A protein, human Carrier Proteins GATA1 Transcription Factor GATA1 protein, human Histones Nuclear Proteins Repressor Proteins SOX6 protein, human SOXD Transcription Factors gamma-Globins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Xu Jian
Children's Hospital Boston, Massachusetts 02115, USA.
Sankaran Vijay G
Ni Min
Menne Tobias F
Puram Rishi V
Kim Woojin
Orkin Stuart H
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
1549-5477
DOI
10.1101/gad.1897310
Published
2010-04-15
Pages
783-98
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2854393
Subset
IM
Grants
NHLBI NIH HHS · R01 HL032259 · United States
NIGMS NIH HHS · T32 GM007753 · United States
Howard Hughes Medical Institute · United States
External Links
PubMed source DOI: 10.1101/gad.1897310 PMC Full Text View journal details
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