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

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.Kay Kendall Leukaemia FundHoward Hughes Medical Institute (Investigator)National Heart, Lung, and Blood InstituteNational Institute of Diabetes and Digestive and Kidney Diseases (U.S.)National Institutes of Health (U.S.)Helen Hay Whitney Foundation (HHMI fellow)National Institutes of Health (U.S.) (Medical Scientist Training Program Award