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Science (New York, N.Y.)
Jun 26, 2015;348 (6242): 1481-1485.

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

Iva A Tchasovnikarova, Richard T Timms, Nicholas J Matheson, Kim Wals, Robin Antrobus, Berthold Göttgens, Gordon Dougan, Mark A Dawson, Paul J Lehner
Author Information
  1. Iva A Tchasovnikarova: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
  2. Richard T Timms: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
  3. Nicholas J Matheson: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
  4. Kim Wals: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
  5. Robin Antrobus: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
  6. Berthold Göttgens: Department of Haematology, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
  7. Gordon Dougan: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
  8. Mark A Dawson: Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.
  9. Paul J Lehner: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
PMID: 26022416 DOI: 10.1126/science.aaa7227

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.

Associated Data

GEO | GSE60056; GSE63116
SRA | PRJNA257239

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Grants

  1. 101835/Wellcome Trust
  2. 12765/Cancer Research UK
  3. 100140/Wellcome Trust
  4. MC_PC_12009/Medical Research Council
  5. 97922/Wellcome Trust
  6. 101835/Z/13/Z/Wellcome Trust

MeSH Term

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

Chemicals

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
Journal Article Research Support, Non-U.S. Gov't

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