論文 - 詳細
| RRC ID | 77334 |
|---|---|
| 著者 | King AJ, Songdej D, Downes DJ, Beagrie RA, Liu S, Buckley M, Hua P, Suciu MC, Marieke Oudelaar A, Hanssen LLP, Jeziorska D, Roberts N, Carpenter SJ, Francis H, Telenius J, Olijnik AA, Sharpe JA, Sloane-Stanley J, Eglinton J, Kassouf MT, Orkin SH, Pennacchio LA, Davies JOJ, Hughes JR, Higgs DR, Babbs C. |
| タイトル | Reactivation of a developmentally silenced embryonic globin gene. |
| ジャーナル | Nat Commun |
| Abstract |
The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues. |
| 巻・号 | 12(1) |
| ページ | 4439 |
| 公開日 | 2021-7-21 |
| DOI | 10.1038/s41467-021-24402-3 |
| PII | 10.1038/s41467-021-24402-3 |
| PMID | 34290235 |
| PMC | PMC8295333 |
| MeSH | Acetylation Animals Chromatin / metabolism DNA-Binding Proteins / metabolism Enhancer Elements, Genetic Erythroid Cells / metabolism Gene Expression Regulation, Developmental* / drug effects Gene Silencing* / drug effects Histone Deacetylase Inhibitors / pharmacology Humans Mice Repressor Proteins / metabolism Transcription Factors / metabolism Transcriptional Activation* / drug effects alpha-Globins / genetics zeta-Globins / genetics* |
| IF | 12.121 |
| 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 | 35 |
| 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) |