Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2.
Nat Genet
; 49(7): 1035-1044, 2017 Jul.
Article
em En
| MEDLINE
| ID: mdl-28581500
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 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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Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Heterocromatina
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Doença de Charcot-Marie-Tooth
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Inativação Gênica
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Montagem e Desmontagem da Cromatina
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Repressão Epigenética
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article