Publication Date:
2015-05-30
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487827/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487827/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tchasovnikarova, Iva A -- Timms, Richard T -- Matheson, Nicholas J -- Wals, Kim -- Antrobus, Robin -- Gottgens, Berthold -- Dougan, Gordon -- Dawson, Mark A -- Lehner, Paul J -- 100140/Wellcome Trust/United Kingdom -- 101835/Wellcome Trust/United Kingdom -- 101835/Z/13/Z/Wellcome Trust/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Jun 26;348(6242):1481-5. doi: 10.1126/science.aaa7227. Epub 2015 May 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK. ; Department of Haematology, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK. ; Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. ; Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, UK. pjl30@cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26022416" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigens, Neoplasm/genetics/*metabolism
;
*Chromosomal Position Effects
;
Conserved Sequence
;
Drosophila melanogaster/genetics/metabolism
;
Evolution, Molecular
;
*Gene Silencing
;
Genes, Reporter
;
Genetic Loci
;
Green Fluorescent Proteins/genetics
;
HeLa Cells
;
Heterochromatin/metabolism
;
Histones/*metabolism
;
Humans
;
Immunoprecipitation
;
Multiprotein Complexes/genetics/*metabolism
;
Nuclear Proteins/genetics/*metabolism
;
Phosphoproteins/genetics/*metabolism
;
Protein Methyltransferases/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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