title: Position-effect variegation revisited: HUSHing up heterochromatin in human cells.
abstract: Much of what we understand about heterochromatin formation in mammals has been extrapolated from forward genetic screens for modifiers of position-effect variegation (PEV) in the fruit fly Drosophila melanogaster. The recent identification of the HUSH (Human Silencing Hub) complex suggests that more recent evolutionary developments contribute to the mechanisms underlying PEV in human cells. Although HUSH-mediated repression also involves heterochromatin spreading through the reading and writing of the repressive H3K9me3 histone modification, clear orthologues of HUSH subunits are not found in Drosophila but are conserved in vertebrates. Here we compare the insights into the mechanisms of PEV derived from genetic screens in the fly, the mouse and in human cells, review what is currently known about the HUSH complex and discuss the implications of HUSH-mediated silencing for viral latency. Future studies will provide mechanistic insight into HUSH complex function and reveal the relationship between HUSH and other epigenetic silencing complexes.
authors: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
authors: Richard T
authors: RT
authors: Timms
authors: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
authors: Iva A
authors: IA
authors: Tchasovnikarova
authors: Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
authors: Paul J
authors: PJ
authors: Lehner
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D005075:Biological Evolution; D045744:Cell Line, Tumor; D055012:Chromosomal Position Effects; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D005820:Genetic Testing; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006238:Haploidy; D006570:Heterochromatin / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D017735:Virus Latency
chemical_list: D000951:Antigens, Neoplasm; D006570:Heterochromatin; D006657:Histones; C547278:MPHOSPH8 protein, human; D009687:Nuclear Proteins; C478775:PPHLN1 protein, human; D010750:Phosphoproteins; C000599477:TASOR protein, human
keywords: HUSH complex; haploid genetic screen; heterochromatin; position-effect variegation; retroviral silencing