| RRC ID |
69376
|
| 著者 |
Liu N, Xu S, Yao Q, Zhu Q, Kai Y, Hsu JY, Sakon P, Pinello L, Yuan GC, Bauer DE, Orkin SH.
|
| タイトル |
Transcription factor competition at the γ-globin promoters controls hemoglobin switching.
|
| ジャーナル |
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.
|
| 巻・号 |
53(4)
|
| ページ |
511-520
|
| 公開日 |
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
|
| リソース情報 |
| ヒト・動物細胞 |
HUDEP-1(RCB4556)
HUDEP-2(RCB4557) |
