title: ATF7IP-Mediated Stabilization of the Histone Methyltransferase SETDB1 Is Essential for Heterochromatin Formation by the HUSH Complex.
abstract: The histone methyltransferase SETDB1 plays a central role in repressive chromatin processes, but the functional requirement for its binding partner ATF7IP has remained enigmatic. Here, we show that ATF7IP is essential for SETDB1 stability: nuclear SETDB1 protein is degraded by the proteasome upon ablation of ATF7IP. As a result, ATF7IP is critical for repression that requires H3K9 trimethylation by SETDB1, including transgene silencing by the HUSH complex. Furthermore, we show that loss of ATF7IP phenocopies loss of SETDB1 in genome-wide assays. ATF7IP and SETDB1 knockout cells exhibit near-identical defects in the global deposition of H3K9me3, which results in similar dysregulation of the transcriptome. Overall, these data identify a critical functional role for ATF7IP in heterochromatin formation by regulating SETDB1 abundance in the nucleus.
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Timms
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Iva A
authors.initials: IA
authors.lastname: Tchasovnikarova
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Antrobus
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: Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. Electronic address: pjl30@cam.ac.uk.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lehner
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D004795:Enzyme Stability; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D020868:Gene Silencing; D006367:HeLa Cells; D006570:Heterochromatin / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D046912:Multiprotein Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000378:metabolism*; D059748:Proteolysis; D012097:Repressor Proteins; D014157:Transcription Factors / Q000378:metabolism*; D059467:Transcriptome / Q000235:genetics
chemical_list: C501309:ATF7IP protein, human; D006570:Heterochromatin; D006657:Histones; D046912:Multiprotein Complexes; D012097:Repressor Proteins; D014157:Transcription Factors; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human; D046988:Proteasome Endopeptidase Complex; D008239:Lysine
keywords: ATF7IP; H3K9me3; HUSH complex; SETDB1; epigenetic silencing; heterochromatin; histone methylation; ubiquitin-mediated degradation