Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6
- Jian Xu1,2,3,
- Vijay G. Sankaran1,2,4,
- Min Ni5,
- Tobias F. Menne1,2,
- Rishi V. Puram4,
- Woojin Kim1,2 and
- Stuart H. Orkin1,2,3,6
- 1Division of Hematology/Oncology, Children's Hospital Boston, Boston, Massachusetts 02115, USA;
- 2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 3Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA;
- 4Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts 02115, USA;
- 5Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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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Footnotes
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↵6 Corresponding author.
E-MAIL stuart_orkin{at}dfci.harvard.edu; FAX (617) 632-4367.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1897310.
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Supplemental material is available at http://www.genesdev.org.
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- Received December 16, 2009.
- Accepted February 24, 2010.
Freely available online through the Genes & Development Open Access option.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press