Hyperactivation of HUSH complex function by Charcot–Marie–Tooth disease mutation in MORC2

• Published in: Nature genetics Vol. 49; no. 7; pp. 1035 - 1044
• Main Authors: Tchasovnikarova, Iva A, Timms, Richard T, Douse, Christopher H, Roberts, Rhys C, Dougan, Gordon, Kingston, Robert E, Modis, Yorgo, Lehner, Paul J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2017; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/31; 14/19; 38/15; 38/22; 38/23; 38/70; 38/88; 38/90; 38/91; 42/47; 631/208/177; 631/337/176; 692/699/375/430; 82/83; Adenosine triphosphatase; Adenosine Triphosphatases - metabolism; Agriculture; Analysis; Animal Genetics and Genomics; Biomedicine; Cancer Research; Charcot-Marie-Tooth disease; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - metabolism; Chromatin; Chromatin Assembly and Disassembly - genetics; CRISPR; CRISPR-Cas Systems; Derepression; Epigenetic Repression - genetics; Epigenetics; Gene Function; Gene Silencing; Genetic aspects; Genetic screening; Genetic testing; Genomes; HeLa Cells; Heterochromatin; Heterochromatin - genetics; Heterochromatin - metabolism; Histone Code; Histone-Lysine N-Methyltransferase; Histones - metabolism; Human Genetics; Humans; Hyperactivity; Lysine - chemistry; Methylation; Multiprotein Complexes; Mutation; Mutation, Missense; Neurons - metabolism; Protein Domains; Protein Interaction Mapping; Protein Methyltransferases - metabolism; Protein Processing, Post-Translational; Proteins; Transcription; Transcription Factors - genetics; Transcription Factors - physiology; Transgenes
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3878

Paul Lehner and colleagues identify an essential role for MORC2 in HUSH complex–mediated epigenetic silencing. They show that loss of MORC2 causes chromatin decompaction at HUSH-target loci and that a MORC2 mutation that causes Charcot–Marie–Tooth disease results in hyperactivation of HUSH-mediated repression in neuronal cells. Dominant mutations in the MORC2 gene have recently been shown to cause axonal Charcot–Marie–Tooth (CMT) disease, but the cellular function of MORC2 is poorly understood. Here, through a genome-wide CRISPR–Cas9-mediated forward genetic screen, we identified MORC2 as an essential gene required for epigenetic silencing by the HUSH complex. HUSH recruits MORC2 to target sites in heterochromatin. We exploited a new method, differential viral accessibility (DIVA), to show that loss of MORC2 results in chromatin decompaction at these target loci, which is concomitant with a loss of H3K9me3 deposition and transcriptional derepression. The ATPase activity of MORC2 is critical for HUSH-mediated silencing, and the most common alteration affecting the ATPase domain in CMT patients (p.Arg252Trp) hyperactivates HUSH-mediated repression in neuronal cells. These data define a critical role for MORC2 in epigenetic silencing by the HUSH complex and provide a mechanistic basis underpinning the role of MORC2 mutations in CMT disease.