2. Academic Validation
  3. ZNF410 represses fetal globin by singular control of CHD4

ZNF410 represses fetal globin by singular control of CHD4

  • Nat Genet. 2021 May;53(5):719-728. doi: 10.1038/s41588-021-00843-w.
Divya S Vinjamur 1,  Qiuming Yao 1 2,  Mitchel A Cole 1,  Connor McGuckin 1,  Chunyan Ren 1,  Jing Zeng 1,  Mir Hossain 1,  Kevin Luk 3,  Scot A Wolfe 3,  Luca Pinello 2,  Daniel E Bauer 4
Affiliations

Affiliations

  • 1 Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • 2 Molecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Department of Pathology, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Molecular, Cell and Cancer Biology, Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA.
  • 4 Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA, USA. bauer@bloodgroup.tch.harvard.edu.
PMID: 33859416 DOI: 10.1038/s41588-021-00843-w
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.

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