Transcription factor competition at the γ-globin promoters controls hemoglobin switching
- 1 March 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 53 (4), 511-520
- https://doi.org/10.1038/s41588-021-00798-y
Abstract
BCL11A, the major regulator of fetal hemoglobin (HbF, α2γ2) level, represses γ-globin expression through direct promoter binding in adult erythroid cells in a switch to adult hemoglobin (HbA, α2β2). To uncover how BCL11A initiates repression, we used CRISPR–Cas9, dCas9, dCas9-KRAB and dCas9-VP64 screens to dissect the γ-globin promoters and identified an activator element near the BCL11A-binding site. Using CUT&RUN and base editing, we demonstrate that a proximal CCAAT box is occupied by the activator NF-Y. BCL11A competes with NF-Y binding through steric hindrance to initiate repression. Occupancy of NF-Y is rapidly established following BCL11A depletion, and precedes γ-globin derepression and locus control region (LCR)–globin loop formation. Our findings reveal that the switch from fetal to adult globin gene expression within the >50-kb β-globin gene cluster is initiated by competition between a stage-selective repressor and a ubiquitous activating factor within a remarkably discrete region of the γ-globin promoters.Funding Information
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (R01HL032259, P01HL032262, P01HL032262, DP2HL137300)
- Howard Hughes Medical Institute
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (K99DK120925)
- U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (R01HG009663, R35HG010717)
- Burroughs Wellcome Fund
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