| Literature DB >> 33301730 |
Xianjiang Lan1, Ren Ren2, Ruopeng Feng3, Lana C Ly4, Yemin Lan5, Zhe Zhang6, Nicholas Aboreden5, Kunhua Qin1, John R Horton2, Jeremy D Grevet7, Thiyagaraj Mayuranathan3, Osheiza Abdulmalik1, Cheryl A Keller8, Belinda Giardine8, Ross C Hardison8, Merlin Crossley4, Mitchell J Weiss3, Xiaodong Cheng2, Junwei Shi9, Gerd A Blobel10.
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.Entities:
Keywords: CHD4; CRISPR screen; NuRD; ZNF410; erythroid biology; fetal hemoglobin; hemoglobin switching; sickle cell disease; transcription; transcription factor
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Year: 2020 PMID： 33301730 PMCID： PMC8556680 DOI： 10.1016/j.molcel.2020.11.006
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 19.328