Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2
(2017) In Nature Genetics 49(7). p.1035-1044- 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 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... (More)
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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- author
- Tchasovnikarova, Iva A ; Timms, Richard T ; Douse, Christopher H LU ; Roberts, Rhys C ; Dougan, Gordon ; Kingston, Robert E ; Modis, Yorgo and Lehner, Paul J
- organization
- publishing date
- 2017-07
- type
- Contribution to journal
- publication status
- published
- keywords
- Adenosine Triphosphatases/metabolism, CRISPR-Cas Systems, Charcot-Marie-Tooth Disease/genetics, Chromatin Assembly and Disassembly/genetics, Epigenetic Repression/genetics, Gene Silencing, HeLa Cells, Heterochromatin/genetics, Histone Code, Histone-Lysine N-Methyltransferase, Histones/metabolism, Humans, Lysine/chemistry, Methylation, Multiprotein Complexes, Mutation, Missense, Neurons/metabolism, Protein Domains, Protein Interaction Mapping, Protein Methyltransferases/metabolism, Protein Processing, Post-Translational, Transcription Factors/genetics, Transgenes
- in
- Nature Genetics
- volume
- 49
- issue
- 7
- pages
- 1035 - 1044
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:28581500
- scopus:85021723165
- ISSN
- 1546-1718
- DOI
- 10.1038/ng.3878
- language
- English
- LU publication?
- yes
- id
- f87a4238-f624-4637-8167-4423ed314d18
- date added to LUP
- 2022-09-16 10:38:25
- date last changed
- 2024-05-02 23:17:52
@article{f87a4238-f624-4637-8167-4423ed314d18,
abstract = {{<p>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.</p>}},
author = {{Tchasovnikarova, Iva A and Timms, Richard T and Douse, Christopher H and Roberts, Rhys C and Dougan, Gordon and Kingston, Robert E and Modis, Yorgo and Lehner, Paul J}},
issn = {{1546-1718}},
keywords = {{Adenosine Triphosphatases/metabolism; CRISPR-Cas Systems; Charcot-Marie-Tooth Disease/genetics; Chromatin Assembly and Disassembly/genetics; Epigenetic Repression/genetics; Gene Silencing; HeLa Cells; Heterochromatin/genetics; Histone Code; Histone-Lysine N-Methyltransferase; Histones/metabolism; Humans; Lysine/chemistry; Methylation; Multiprotein Complexes; Mutation, Missense; Neurons/metabolism; Protein Domains; Protein Interaction Mapping; Protein Methyltransferases/metabolism; Protein Processing, Post-Translational; Transcription Factors/genetics; Transgenes}},
language = {{eng}},
number = {{7}},
pages = {{1035--1044}},
publisher = {{Nature Publishing Group}},
series = {{Nature Genetics}},
title = {{Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2}},
url = {{http://dx.doi.org/10.1038/ng.3878}},
doi = {{10.1038/ng.3878}},
volume = {{49}},
year = {{2017}},
}