Reference - Detail
| 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 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 21 |
| Altmetric score changes over past 6months | 3.0 |
| Resource | |
| Human and Animal Cells | HUDEP-1(RCB4556) HUDEP-2(RCB4557) |