Journal
CELL
Volume 173, Issue 2, Pages 430-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.03.016
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Funding
- Howard Hughes Medical Institute (HHMI)
- National Heart, Lung, and Blood Institute (NHLBI) [R01 HL119099, R01 HL032259]
- National Human Genome Research Institute (NHGR) [HG003985I]
- National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) [K01 DK093543, R03 DK109232]
- Doris Duke Charitable Foundation Innovations in Clinical Research Award
- Cooley's Anemia Foundation Fellowship
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Fetal hemoglobin (HbF, alpha(2)gamma(2)) level is genetically controlled and modifies severity of adult hemoglobin (HbA, alpha(2)gamma(2)) disorders, sickle cell disease, and beta-thalassemia. Common genetic variation affects expression of BCL11A, a regulator of HbF silencing. To uncover how BCL11A supports the developmental switch from gamma- to beta-globin, we use a functional assay and protein binding microarray to establish a requirement for a zinc-finger cluster in BCL11A in repression and identify a preferred DNA recognition sequence. This motif appears in embryonic and fetal-expressed globin promoters and is duplicated in gamma-globin promoters. The more distal of the duplicated motifs is mutated in individuals with hereditary persistence of HbF. Using the CUT&RUN approach to map protein binding sites in erythroid cells, we demonstrate BCL11A occupancy preferentially at the distal motif, which can be disrupted by editing the promoter. Our findings reveal that direct gamma-globin gene promoter repression by BCL11A underlies hemoglobin switching.
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