Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6
Author(s)Xu, Jian; Sankaran, Vijay G.; Ni, Min; Menne, Tobias F.; Puram, Rishi Venkata; Kim, Woojin; Orkin, Stuart H.; ... Show more Show less
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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.
DepartmentHarvard University--MIT Division of Health Sciences and Technology
Genes & Development
Cold Spring Harbor Laboratory Press
Xu, J., V. G. Sankaran, M. Ni, T. F. Menne, R. V. Puram, W. Kim, and S. H. Orkin. “Transcriptional Silencing of γ-Globin by BCL11A Involves Long-Range Interactions and Cooperation with SOX6.” Genes & Development 24, no. 8 (April 15, 2010): 783–798.
Final published version