論文 - 詳細
| RRC ID | 67334 |
|---|---|
| 著者 | Doerfler PA, Feng R, Li Y, Palmer LE, Porter SN, Bell HW, Crossley M, Pruett-Miller SM, Cheng Y, Weiss MJ. |
| タイトル | Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin. |
| ジャーナル | Nat Genet |
| Abstract |
Hereditary persistence of fetal hemoglobin (HPFH) ameliorates β-hemoglobinopathies by inhibiting the developmental switch from γ-globin (HBG1/HBG2) to β-globin (HBB) gene expression. Some forms of HPFH are associated with γ-globin promoter variants that either disrupt binding motifs for transcriptional repressors or create new motifs for transcriptional activators. How these variants sustain γ-globin gene expression postnatally remains undefined. We mapped γ-globin promoter sequences functionally in erythroid cells harboring different HPFH variants. Those that disrupt a BCL11A repressor binding element induce γ-globin expression by facilitating the recruitment of nuclear transcription factor Y (NF-Y) to a nearby proximal CCAAT box and GATA1 to an upstream motif. The proximal CCAAT element becomes dispensable for HPFH variants that generate new binding motifs for activators NF-Y or KLF1, but GATA1 recruitment remains essential. Our findings define distinct mechanisms through which transcription factors and their cis-regulatory elements activate γ-globin expression in different forms of HPFH, some of which are being recreated by therapeutic genome editing. |
| 巻・号 | 53(8) |
| ページ | 1177-1186 |
| 公開日 | 2021-8-1 |
| DOI | 10.1038/s41588-021-00904-0 |
| PII | 10.1038/s41588-021-00904-0 |
| PMID | 34341563 |
| PMC | PMC8610173 |
| MeSH | Animals Binding Sites CCAAT-Binding Factor / genetics* COS Cells CRISPR-Cas Systems Cell Line Chlorocebus aethiops Erythroid Cells Fetal Hemoglobin / genetics* GATA1 Transcription Factor / genetics* Gene Editing / methods Gene Expression Regulation, Developmental Humans Promoter Regions, Genetic Repressor Proteins / genetics Repressor Proteins / metabolism gamma-Globins / genetics* |
| IF | 27.605 |
| 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 | 24 |
| 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) |