Transcription factor competition at the γ-globin promoters controls hemoglobin switching.
Nat Genet
; 53(4): 511-520, 2021 04.
Article
em En
| MEDLINE
| ID: mdl-33649594
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, α2ß2). 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 ß-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.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
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Hemoglobina Fetal
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Hemoglobina A
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Regiões Promotoras Genéticas
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Fator de Ligação a CCAAT
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Gama-Globinas
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article