GENE SILENCING. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells

Science. 2015 Jun 26;348(6242):1481-1485. doi: 10.1126/science.aaa7227. Epub 2015 May 28.

Abstract

Forward genetic screens in Drosophila melanogaster for modifiers of position-effect variegation have revealed the basis of much of our understanding of heterochromatin. We took an analogous approach to identify genes required for epigenetic repression in human cells. A nonlethal forward genetic screen in near-haploid KBM7 cells identified the HUSH (human silencing hub) complex, comprising three poorly characterized proteins, TASOR, MPP8, and periphilin; this complex is absent from Drosophila but is conserved from fish to humans. Loss of HUSH components resulted in decreased H3K9me3 both at endogenous genomic loci and at retroviruses integrated into heterochromatin. Our results suggest that the HUSH complex is recruited to genomic loci rich in H3K9me3, where subsequent recruitment of the methyltransferase SETDB1 is required for further H3K9me3 deposition to maintain transcriptional silencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism*
  • Chromosomal Position Effects*
  • Conserved Sequence
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Evolution, Molecular
  • Gene Silencing*
  • Genes, Reporter
  • Genetic Loci
  • Green Fluorescent Proteins / genetics
  • HeLa Cells
  • Heterochromatin / metabolism
  • Histone-Lysine N-Methyltransferase
  • Histones / metabolism*
  • Humans
  • Immunoprecipitation
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Methyltransferases / metabolism

Substances

  • Antigens, Neoplasm
  • Heterochromatin
  • Histones
  • MPHOSPH8 protein, human
  • Multiprotein Complexes
  • Nuclear Proteins
  • PPHLN1 protein, human
  • Phosphoproteins
  • TASOR protein, human
  • green fluorescent protein, Aequorea victoria
  • Green Fluorescent Proteins
  • Protein Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • SETDB1 protein, human

Associated data

  • GEO/GSE60056
  • GEO/GSE63116
  • SRA/PRJNA257239