Dominant mutations in the MORC2 gene have recently been shown to cause axonal Charcot–Marie–Tooth (CMT) disease. CMT is one of the hereditary motor and sensory neuropathies, a group of varied inherited disorders of the peripheral nervous system characterised by progressive loss of muscle tissue and touch sensation across various parts of the body.
The cellular function of MORC2 is poorly understood. In a genome-wide CRISPR–Cas9 forward genetic screen the Modis and Lehner groups from the Department of Medicine identified MORC2 as an essential gene required for epigenetic silencing by the HUSH complex. They recently characterised HUSH as a novel epigenetic complex required for silencing newly integrated retroviruses. They now find HUSH recruits MORC2 to target sites in heterochromatin. By developing a new method, differential viral accessibility (DIVA), they 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. Their 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. The work has been published in Nature Genetics. https://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3878.html
MORC2 is required for transgene silencing by the HUSH complex in HeLa cells. Top row: In wild type cells, MORC2 (red) represses expression of a HUSH-repressed GFP reporter. Bottom row: Knockout of MORC2 (with CRISPR–Cas9) results in derepression of the HUSH GFP reporter (green). Nuclei were stained with DAPI (blue).