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 identify MORC2 as an essential gene required for epigenetic silencing by the HUSH complex. HUSH recruits MORC2 to target sites in heterochromatin. We exploit 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 mutation affecting the ATPase domain found in CMT patients (R252W) hyper-activates 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.

Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators

“…5c,d). HUSH KO in K562 cells almost completely abrogated MORC2 binding at L1s (consistent with recently published observations that HUSH recruits MORC2 for transcriptional repression 21 ), whereas MORC2 deletion led to a modest, but appreciable decrease of HUSH subunit binding (Extended Data Fig. 6).…”

“…3b). MORC2, which has recently been shown to biochemically and functionally interact with HUSH 21 , is a member of the microrchidia (MORC) protein family that has been implicated in transposon silencing in plants and mice 22,23 . While MORC2/HUSH have been previously implicated in heterochromatin formation, most heterochromatin factors had no impact on L1 retrotransposition, suggesting a selective effect (Fig.…”

TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control

“…The activity of TASOR is critical in early development: the homozygous mutation L130P, at a conserved leucine in mouse TASOR (identified as MommeD6), is lethal in embryos before gastrulation (Harten et al, 2014). The HUSH complex recruits the H3K9 methyltransferase SET domain bifurcated 1 (SETDB1) to deposit H3K9me3 (Tchasovnikarova et al, 2015) and the ATPase MORC2 to compact chromatin (Douse et al, 2018;Tchasovnikarova et al, 2017). HUSH is a vertebrate-specific chromatin regulator that represses both exogenous and endogenous genetic elements.…”

Histone methyltransferase SETDB1 contributes to melanoma tumorigenesis and serves as a new potential therapeutic target

“…The human silencing hub (HUSH) complex localizes to genomic regions harboring the repressive histone modification H3K9me3. HUSH complex recruits SETDB1 to these sites, which increases the levels of H3K9me3 …”

“…HUSH complex recruits SETDB1 to these sites, which increases the levels of H3K9me3. 9 Deregulation of HKMT expression can cause a disruption in normal differentiation and may increase the aggressiveness of cancer. 10,11 Furthermore, aberrant SETDB1 expression has also been shown to contribute to tumorigenesis in a zebrafish model of melanoma.…”