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

ABSTRACT: Hyper-activation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2

PROVIDER: PRJNA377238 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5296140.fastq.gz	Fastqsanger.gz
	SRR5296150.fastq.gz	Fastqsanger.gz
	SRR5296160.fastq.gz	Fastqsanger.gz
	SRR5296141.fastq.gz	Fastqsanger.gz
	SRR5296151.fastq.gz	Fastqsanger.gz

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Assessing the impact of the R252W Charcot-Marie-Tooth disease mutation in MORC2 on HUSH-mediated repression

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

Project description:This SuperSeries is composed of the SubSeries listed below.

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

Project description: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.

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DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex

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