2. Academic Validation
  3. ZNF410 Uniquely Activates the NuRD Component CHD4 to Silence Fetal Hemoglobin Expression

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.
Xianjiang Lan 1,  Ren Ren 2,  Ruopeng Feng 3,  Lana C Ly 4,  Yemin Lan 5,  Zhe Zhang 6,  Nicholas Aboreden 5,  Kunhua Qin 1,  John R Horton 2,  Jeremy D Grevet 7,  Thiyagaraj Mayuranathan 3,  Osheiza Abdulmalik 1,  Cheryl A Keller 8,  Belinda Giardine 8,  Ross C Hardison 8,  Merlin Crossley 4,  Mitchell J Weiss 3,  Xiaodong Cheng 2,  Junwei Shi 9,  Gerd A Blobel 10
Affiliations

Affiliations

  • 1 Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 2 Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 3 Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 4 School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, NSW 2052, Australia.
  • 5 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6 Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 7 Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 8 Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
  • 9 Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: [email protected].
  • 10 Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: [email protected].
PMID: 33301730 DOI: 10.1016/j.molcel.2020.11.006
Abstract

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.

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