RRC ID 69376
Author Liu N, Xu S, Yao Q, Zhu Q, Kai Y, Hsu JY, Sakon P, Pinello L, Yuan GC, Bauer DE, Orkin SH.
Title Transcription factor competition at the γ-globin promoters controls hemoglobin switching.
Journal Nat Genet
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.
Volume 53(4)
Pages 511-520
Published 2021-4-1
DOI 10.1038/s41588-021-00798-y
PII 10.1038/s41588-021-00798-y
PMID 33649594
PMC PMC8038971
MeSH Base Sequence Binding Sites Binding, Competitive CCAAT-Binding Factor / chemistry* CCAAT-Binding Factor / genetics CCAAT-Binding Factor / metabolism Erythropoiesis / genetics Fetal Hemoglobin / genetics* Fetal Hemoglobin / metabolism Gene Editing / methods Gene Expression Regulation HEK293 Cells Hemoglobin A / genetics* Hemoglobin A / metabolism Humans Models, Molecular Primary Cell Culture Promoter Regions, Genetic* Protein Binding Protein Conformation, alpha-Helical Protein Conformation, beta-Strand Protein Interaction Domains and Motifs Repressor Proteins / chemistry* Repressor Proteins / genetics Repressor Proteins / metabolism Stem Cells beta-Globins / chemistry beta-Globins / genetics beta-Globins / metabolism gamma-Globins / chemistry* gamma-Globins / genetics gamma-Globins / metabolism
IF 27.605
Human and Animal Cells HUDEP-1(RCB4556) HUDEP-2(RCB4557)