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

Citation:

Nan Liu, Shuqian Xu, Qiuming Yao, Qian Zhu, Yan Kai, Jonathan Y. Hsu, Phraew Sakon, Luca Pinello, Guo-Cheng Yuan, Daniel E. Bauer, and Stuart H. Orkin. 2021. “Transcription factor competition at the γ-globin promoters controls hemoglobin switching.” Nature Genetics, Pp. 1–10.

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 \textgreater50-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.

Notes:

Publisher: Nature Publishing Group