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

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

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.

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • CRISPR-Cas Systems
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / metabolism
  • Chromatin Assembly and Disassembly / genetics*
  • Epigenetic Repression / genetics*
  • Gene Silencing*
  • HeLa Cells
  • Heterochromatin / genetics*
  • Heterochromatin / metabolism
  • Histone Code
  • Histones / metabolism
  • Humans
  • Lysine / chemistry
  • Methylation
  • Multiprotein Complexes
  • Mutation, Missense
  • Neurons / metabolism
  • Protein Domains
  • Protein Interaction Mapping
  • Protein Methyltransferases / metabolism
  • Protein Processing, Post-Translational
  • Transcription Factors / genetics*
  • Transcription Factors / physiology
  • Transgenes

Substances

  • Heterochromatin
  • Histones
  • MORC2 protein, human
  • Multiprotein Complexes
  • Transcription Factors
  • Protein Methyltransferases
  • SETDB1 protein, human
  • Adenosine Triphosphatases
  • Lysine