Unknown

Dataset Information

0

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


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.

SUBMITTER: Liu N 

PROVIDER: S-EPMC8038971 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Liu Nan N   Xu Shuqian S   Yao Qiuming Q   Zhu Qian Q   Kai Yan Y   Hsu Jonathan Y JY   Sakon Phraew P   Pinello Luca L   Yuan Guo-Cheng GC   Bauer Daniel E DE   Orkin Stuart H SH  

Nature genetics 20210301 4


BCL11A, the major regulator of fetal hemoglobin (HbF, α<sub>2</sub>γ<sub>2</sub>) level, represses γ-globin expression through direct promoter binding in adult erythroid cells in a switch to adult hemoglobin (HbA, α<sub>2</sub>β<sub>2</sub>). 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  ...[more]

Similar Datasets

2020-12-22 | GSE150530 | GEO
2020-12-22 | GSE150488 | GEO
2020-12-22 | GSE160456 | GEO
2020-12-22 | GSE150529 | GEO
2020-12-22 | GSE150491 | GEO
2020-12-22 | GSE150490 | GEO
| PRJNA632647 | ENA
| PRJNA632565 | ENA
| PRJNA632567 | ENA
| PRJNA673226 | ENA