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Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2
Iva A Tchasovnikarova1,2, Richard T Timms1, Christopher H Douse3
1Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.
Nature Genetics
|June 6, 2017
Summary
MORC2 is essential for epigenetic silencing by the HUSH complex, maintaining gene repression. Mutations linked to Charcot-Marie-Tooth (CMT) disease disrupt this function, impacting chromatin structure and gene expression.
Area of Science:
- Epigenetics
- Molecular Biology
- Genetics
Background:
- Dominant MORC2 gene mutations cause axonal Charcot-Marie-Tooth (CMT) disease.
- The cellular function of MORC2 remains largely unknown.
Purpose of the Study:
- Identify MORC2's cellular function.
- Elucidate the molecular mechanisms linking MORC2 to CMT disease.
Main Methods:
- Genome-wide CRISPR-Cas9 forward genetic screen.
- Differential viral accessibility (DIVA) assay.
- Analysis of H3K9me3 deposition and chromatin structure.
Main Results:
- MORC2 is essential for HUSH complex-mediated epigenetic silencing.
- MORC2 loss leads to chromatin decompaction, H3K9me3 loss, and transcriptional derepression.
- A common CMT-associated MORC2 mutation (p.Arg252Trp) hyperactivates HUSH-mediated repression.
Conclusions:
- MORC2 plays a critical role in HUSH complex-mediated epigenetic silencing.
- MORC2's ATPase activity is vital for its silencing function.
- These findings provide a mechanistic basis for MORC2 mutations in CMT disease.
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