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

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.

journal_name

Nat Genet

journal_title

Nature genetics

authors

Tchasovnikarova IA,Timms RT,Douse CH,Roberts RC,Dougan G,Kingston RE,Modis Y,Lehner PJ

doi

10.1038/ng.3878

subject

Has Abstract

pub_date

2017-07-01 00:00:00

pages

1035-1044

issue

7

eissn

1061-4036

issn

1546-1718

journal_volume

49

pub_type

杂志文章

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