珠蛋白
转录因子
增强子
分子生物学
抄写(语言学)
基因
转录调控
调节顺序
作者
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
出处
期刊:Nature Genetics
[Springer Nature]
日期:2021-03-01
卷期号:53 (4): 511-520
被引量:12
标识
DOI:10.1038/s41588-021-00798-y
摘要
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. CRISPR–Cas9 tiled screens of the β-globin gene cluster identify an NF-Y bound activator element at the γ-globin promoter. Binding competition by the transcriptional repressor BCL11A leads to NF-Y eviction and a switch from fetal to adult globin gene expression.
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