論文 - 詳細
| RRC ID | 77305 |
|---|---|
| 著者 | Mehta S, Buyanbat A, Kai Y, Karayel O, Goldman SR, Seruggia D, Zhang K, Fujiwara Y, Donovan KA, Zhu Q, Yang H, Nabet B, Gray NS, Mann M, Fischer ES, Adelman K, Orkin SH. |
| タイトル | Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells. |
| ジャーナル | Cell Chem Biol |
| Abstract |
Reactivation of fetal hemoglobin expression by the downregulation of BCL11A is a promising treatment for β-hemoglobinopathies. A detailed understanding of BCL11A-mediated repression of γ-globin gene (HBG1/2) transcription is lacking, as studies to date used perturbations by shRNA or CRISPR-Cas9 gene editing. We leveraged the dTAG PROTAC degradation platform to acutely deplete BCL11A protein in erythroid cells and examined consequences by nascent transcriptomics, proteomics, chromatin accessibility, and histone profiling. Among 31 genes repressed by BCL11A, HBG1/2 and HBZ show the most abundant and progressive changes in transcription and chromatin accessibility upon BCL11A loss. Transcriptional changes at HBG1/2 were detected in <2 h. Robust HBG1/2 reactivation upon acute BCL11A depletion occurred without the loss of promoter 5-methylcytosine (5mC). Using targeted protein degradation, we establish a hierarchy of gene reactivation at BCL11A targets, in which nascent transcription is followed by increased chromatin accessibility, and both are uncoupled from promoter DNA methylation at the HBG1/2 loci. |
| 巻・号 | 29(8) |
| ページ | 1273-1287.e8 |
| 公開日 | 2022-8-18 |
| DOI | 10.1016/j.chembiol.2022.06.007 |
| PII | S2451-9456(22)00239-2 |
| PMID | 35839780 |
| PMC | PMC9391307 |
| MeSH | Carrier Proteins / metabolism Chromatin / genetics Chromatin / metabolism Erythroid Cells / metabolism Nuclear Proteins* / metabolism Proteome* / metabolism Repressor Proteins / genetics Repressor Proteins / metabolism Transcription Factors / metabolism |
| IF | 6.762 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 57 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HUDEP-2(RCB4557) HUDEP-1(RCB4556) |