ZNF410 Uniquely Activates the NuRD Component CHD4 to Silence Fetal Hemoglobin Expression

Mol Cell. 2021 Jan 21;81(2):239-254.e8. doi: 10.1016/j.molcel.2020.11.006. Epub 2020 Dec 9.


Metazoan transcription factors typically regulate large numbers of genes. Here we identify via a CRISPR-Cas9 genetic screen ZNF410, a pentadactyl DNA-binding protein that in human erythroid cells directly activates only a single gene, the NuRD component CHD4. Specificity is conveyed by two highly evolutionarily conserved clusters of ZNF410 binding sites near the CHD4 gene with no counterparts elsewhere in the genome. Loss of ZNF410 in adult-type human erythroid cell culture systems and xenotransplantation settings diminishes CHD4 levels and derepresses the fetal hemoglobin genes. While previously known to be silenced by CHD4, the fetal globin genes are exposed here as among the most sensitive to reduced CHD4 levels.. In vitro DNA binding assays and crystallographic studies reveal the ZNF410-DNA binding mode. ZNF410 is a remarkably selective transcriptional activator in erythroid cells, and its perturbation might offer new opportunities for treatment of hemoglobinopathies.

Keywords: CHD4; CRISPR screen; NuRD; ZNF410; erythroid biology; fetal hemoglobin; hemoglobin switching; sickle cell disease; transcription; transcription factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • COS Cells
  • CRISPR-Cas Systems
  • Chlorocebus aethiops
  • DNA / genetics*
  • DNA / metabolism
  • Erythroid Precursor Cells / cytology
  • Erythroid Precursor Cells / metabolism*
  • Erythroid Precursor Cells / transplantation
  • Fetal Blood / cytology
  • Fetal Blood / metabolism
  • Fetal Hemoglobin / genetics*
  • Fetal Hemoglobin / metabolism
  • Fetus
  • Gene Editing
  • HEK293 Cells
  • Heterografts
  • Humans
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / chemistry
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics*
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
  • Mice
  • Models, Molecular
  • Mouse Embryonic Stem Cells / cytology
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcriptional Activation


  • CHD4 protein, human
  • Transcription Factors
  • ZNF410 protein, human
  • DNA
  • Fetal Hemoglobin
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex