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.

中文翻译：

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MORC2 中的 Charcot-Marie-Tooth 病突变导致 HUSH 复合功能过度激活。

最近显示 MORC2 基因的显性突变会导致轴突 Charcot-Marie-Tooth (CMT) 病，但对 MORC2 的细胞功能知之甚少。在这里，通过全基因组 CRISPR-Cas9 介导的正向遗传筛选，我们将 MORC2 鉴定为 HUSH 复合体表观遗传沉默所需的必需基因。HUSH 招募 MORC2 以靶向异染色质中的位点。我们采用了一种新方法，差异病毒可及性 (DIVA)，表明 MORC2 的缺失会导致这些目标位点的染色质分解，这与 H3K9me3 沉积和转录去阻遏的缺失相伴随。MORC2 的 ATPase 活性对于 HUSH 介导的沉默至关重要，影响 CMT 患者 (p.Arg252Trp) 中 ATPase 结构域的最常见改变会过度激活神经元细胞中 HUSH 介导的抑制。