{"database":"biostudies-literature","file_versions":[],"scores":{"citationCount":0,"reanalysisCount":0,"viewCount":51,"searchCount":0},"additional":{"submitter":["Liu N"],"funding":["NIDDK NIH HHS","Howard Hughes Medical Institute","Burroughs Wellcome Fund","NHLBI NIH HHS","NHGRI NIH HHS","U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute","U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute","U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases"],"pagination":["511-520"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8038971"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["53(4)"],"pubmed_abstract":["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 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."],"journal":["Nature genetics"],"pubmed_title":["Transcription factor competition at the γ-globin promoters controls hemoglobin switching."],"pmcid":["PMC8038971"],"funding_grant_id":["R35 HG010717","R01HL032259","P01HL032262","DP2HL137300","P01 HL032262","R35HG010717","K99DK120925","P30 DK049216","U54 DK106829","R01HG009663","R01 HL032259","DP2 HL137300","R01 HG009663","K99 DK120925"],"pubmed_authors":["Kai Y","Hsu JY","Pinello L","Liu N","Yuan GC","Xu S","Bauer DE","Yao Q","Orkin SH","Zhu Q","Sakon P"],"view_count":["51"],"additional_accession":[]},"is_claimable":false,"name":"Transcription factor competition at the γ-globin promoters controls hemoglobin switching.","description":"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 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.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Apr","modification":"2024-10-15T00:13:04.081Z","creation":"2022-02-11T10:04:58.26Z"},"accession":"S-EPMC8038971","cross_references":{"pubmed":["33649594"],"doi":["10.1038/s41588-021-00798-y"]}}