title: GENE SILENCING. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells.
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.
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Iva A
authors.initials: IA
authors.lastname: Tchasovnikarova
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Timms
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Matheson
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Wals
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Antrobus
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.affiliation: Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dawson
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lehner
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D055012:Chromosomal Position Effects; D017124:Conserved Sequence; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D020868:Gene Silencing; D017930:Genes, Reporter; D056426:Genetic Loci; D049452:Green Fluorescent Proteins / Q000235:genetics; D006367:HeLa Cells; D006570:Heterochromatin / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011496:Protein Methyltransferases / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D006570:Heterochromatin; D006657:Histones; C547278:MPHOSPH8 protein, human; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; C478775:PPHLN1 protein, human; D010750:Phosphoproteins; C000599477:TASOR protein, human; C485192:green fluorescent protein, Aequorea victoria; D049452:Green Fluorescent Proteins; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human