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Nat Genet. 2017 Jul;49(7):1035-1044. doi: 10.1038/ng.3878. Epub 2017 Jun 5.

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

Author information

1
Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.
2
Department of Molecular Biology, Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
3
Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Francis Crick Way, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK.
4
Department of Clinical Neurosciences, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.
5
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
#
Contributed equally

Abstract

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.

PMID:
28581500
PMCID:
PMC5493197
DOI:
10.1038/ng.3878
[Indexed for MEDLINE]
Free PMC Article

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