ZNF410 represses fetal globin by singular control of CHD4
| Autor: | Chunyan Ren, Scot A. Wolfe, Luca Pinello, Qiuming Yao, Jing Zeng, Mitchel A. Cole, Mir A. Hossain, Daniel E. Bauer, Kevin Luk, Connor McGuckin, Divya S. Vinjamur |
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| Rok vydání: | 2021 |
| Předmět: |
Regulation of gene expression
0303 health sciences Repressor Biology Chromatin Cell biology 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases Genetics Nucleosome Globin CHD4 Transcription factor Psychological repression 030217 neurology & neurosurgery 030304 developmental biology |
| Zdroj: | Nature Genetics. 53:719-728 |
| ISSN: | 1546-1718 1061-4036 |
| DOI: | 10.1038/s41588-021-00843-w |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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