Transcription factor competition at the γ-globin promoters controls hemoglobin switching

Nan Liu, Shuqian Xu, Qiuming Yao, Qian Zhu, Yan Kai, Jonathan Y. Hsu, Phraew Sakon, Luca Pinello, Guo Cheng Yuan, Daniel E. Bauer, Stuart H. Orkin

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish
Pages (from-to)511-520
Number of pages10
JournalNature Genetics
Volume53
Issue number4
DOIs
StatePublished - Apr 2021

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