RRC ID |
69381
|
著者 |
Vinjamur DS, Yao Q, Cole MA, McGuckin C, Ren C, Zeng J, Hossain M, Luk K, Wolfe SA, Pinello L, Bauer DE.
|
タイトル |
ZNF410 represses fetal globin by singular control of CHD4.
|
ジャーナル |
Nat Genet
|
Abstract |
Known fetal hemoglobin (HbF) silencers have potential on-target liabilities for rational β-hemoglobinopathy therapeutic inhibition. Here, through transcription factor (TF) CRISPR screening, we identify zinc-finger protein (ZNF) 410 as an HbF repressor. ZNF410 does not bind directly to the genes encoding γ-globins, but rather its chromatin occupancy is concentrated solely at CHD4, encoding the NuRD nucleosome remodeler, which is itself required for HbF repression. CHD4 has two ZNF410-bound regulatory elements with 27 combined ZNF410 binding motifs constituting unparalleled genomic clusters. These elements completely account for the effects of ZNF410 on fetal globin repression. Knockout of ZNF410 or its mouse homolog Zfp410 reduces CHD4 levels by 60%, enough to substantially de-repress HbF while eluding cellular or organismal toxicity. These studies suggest a potential target for HbF induction for β-hemoglobin disorders with a wide therapeutic index. More broadly, ZNF410 represents a special class of gene regulator, a conserved TF with singular devotion to regulation of a chromatin subcomplex.
|
巻・号 |
53(5)
|
ページ |
719-728
|
公開日 |
2021-5-1
|
DOI |
10.1038/s41588-021-00843-w
|
PII |
10.1038/s41588-021-00843-w
|
PMID |
33859416
|
PMC |
PMC8180380
|
MeSH |
Adult
Animals
Base Sequence
CRISPR-Cas Systems / genetics
Cells, Cultured
Chromatin / metabolism
DNA / metabolism
Erythroid Cells / metabolism
Erythropoiesis
Fetal Hemoglobin / metabolism*
Gene Editing
Gene Expression Regulation
Hematopoiesis
Hematopoietic Stem Cells / metabolism
Humans
Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism*
Mice
Mutagenesis / genetics
Protein Binding
Reproducibility of Results
Transcription Factors / metabolism*
|
IF |
27.605
|
リソース情報 |
ヒト・動物細胞 |
HUDEP-2(RCB4557) |