| RRC ID |
72851
|
| 著者 |
Feng R, Mayuranathan T, Huang P, Doerfler PA, Li Y, Yao Y, Zhang J, Palmer LE, Mayberry K, Christakopoulos GE, Xu P, Li C, Cheng Y, Blobel GA, Simon MC, Weiss MJ.
|
| タイトル |
Activation of γ-globin expression by hypoxia-inducible factor 1α.
|
| ジャーナル |
Nature
|
| Abstract |
Around birth, globin expression in human red blood cells (RBCs) shifts from γ-globin to β-globin, which results in fetal haemoglobin (HbF, α2γ2) being gradually replaced by adult haemoglobin (HbA, α2β2)1. This process has motivated the development of innovative approaches to treat sickle cell disease and β-thalassaemia by increasing HbF levels in postnatal RBCs2. Here we provide therapeutically relevant insights into globin gene switching obtained through a CRISPR-Cas9 screen for ubiquitin-proteasome components that regulate HbF expression. In RBC precursors, depletion of the von Hippel-Lindau (VHL) E3 ubiquitin ligase stabilized its ubiquitination target, hypoxia-inducible factor 1α (HIF1α)3,4, to induce γ-globin gene transcription. Mechanistically, HIF1α-HIF1β heterodimers bound cognate DNA elements in BGLT3, a long noncoding RNA gene located 2.7 kb downstream of the tandem γ-globin genes HBG1 and HBG2. This was followed by the recruitment of transcriptional activators, chromatin opening and increased long-range interactions between the γ-globin genes and their upstream enhancer. Similar induction of HbF occurred with hypoxia or with inhibition of prolyl hydroxylase domain enzymes that target HIF1α for ubiquitination by the VHL E3 ubiquitin ligase. Our findings link globin gene regulation with canonical hypoxia adaptation, provide a mechanism for HbF induction during stress erythropoiesis and suggest a new therapeutic approach for β-haemoglobinopathies.
|
| 巻・号 |
610(7933)
|
| ページ |
783-790
|
| 公開日 |
2022-10-1
|
| DOI |
10.1038/s41586-022-05312-w
|
| PII |
10.1038/s41586-022-05312-w
|
| PMID |
36224385
|
| MeSH |
Chromatin
Erythropoiesis
Fetal Hemoglobin / biosynthesis
Fetal Hemoglobin / genetics
Humans
Hypoxia / genetics
Prolyl Hydroxylases / metabolism
Proteasome Endopeptidase Complex / metabolism
RNA, Long Noncoding
Ubiquitin / metabolism
Ubiquitin-Protein Ligases / genetics
gamma-Globins* / biosynthesis
gamma-Globins* / genetics
|
| IF |
42.779
|
| リソース情報 |
| ヒト・動物細胞 |
HUDEP-2(RCB4557) |
