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Hyperactivation of ...
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Tchasovnikarova, Iva A
(författare)
Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2
- Artikel/kapitelEngelska2017
Förlag, utgivningsår, omfång ...
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2017-06-05
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Springer Science and Business Media LLC,2017
Nummerbeteckningar
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LIBRIS-ID:oai:lup.lub.lu.se:f87a4238-f624-4637-8167-4423ed314d18
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https://lup.lub.lu.se/record/f87a4238-f624-4637-8167-4423ed314d18URI
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https://doi.org/10.1038/ng.3878DOI
Kompletterande språkuppgifter
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Språk:engelska
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Sammanfattning på:engelska
Ingår i deldatabas
Klassifikation
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Ämneskategori:art swepub-publicationtype
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Ämneskategori:ref swepub-contenttype
Anmärkningar
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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.
Ämnesord och genrebeteckningar
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Adenosine Triphosphatases/metabolism
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CRISPR-Cas Systems
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Charcot-Marie-Tooth Disease/genetics
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Chromatin Assembly and Disassembly/genetics
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Epigenetic Repression/genetics
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Gene Silencing
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HeLa Cells
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Heterochromatin/genetics
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Histone Code
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Histone-Lysine N-Methyltransferase
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Histones/metabolism
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Humans
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Lysine/chemistry
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Methylation
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Multiprotein Complexes
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Mutation, Missense
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Neurons/metabolism
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Protein Domains
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Protein Interaction Mapping
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Protein Methyltransferases/metabolism
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Protein Processing, Post-Translational
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Transcription Factors/genetics
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Transgenes
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Timms, Richard T
(författare)
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Douse, Christopher HLund University,Lunds universitet,Epigenetik och kromatindynamik,Forskargrupper vid Lunds universitet,Epigenetics and Chromatin Dynamics,Lund University Research Groups,University of Cambridge(Swepub:lu)ch2676do
(författare)
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Roberts, Rhys C
(författare)
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Dougan, Gordon
(författare)
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Kingston, Robert E
(författare)
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Modis, Yorgo
(författare)
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Lehner, Paul J
(författare)
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Epigenetik och kromatindynamikForskargrupper vid Lunds universitet
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Nature Genetics: Springer Science and Business Media LLC49:7, s. 1035-10441546-17181061-4036
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