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

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.
Iva A Tchasovnikarova # 1,  Richard T Timms # 1,  Nicholas J Matheson 1,  Kim Wals 1,  Robin Antrobus 1,  Berthold Göttgens 2,  Gordon Dougan 3,  Mark A Dawson 4,  Paul J Lehner 1
Affiliations

Affiliations

  • 1 Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
  • 2 Department of Haematology, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
  • 3 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
  • 4 Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.
  • # Contributed equally.
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.

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