Structural highlights
Disease
[MORC2_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.
Function
[MORC2_HUMAN] Exhibits a cytosolic function in lipogenesis, adipogenic differentiation, and lipid homeostasis by increasing the activity of ACLY, possibly preventing its dephosphorylation (PubMed:24286864). May act as a transcriptional repressor (PubMed:20225202). Down-regulates CA9 expression (PubMed:20110259).[1] [2] [3]
Publication Abstract from PubMed
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.
Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2.,Tchasovnikarova IA, Timms RT, Douse CH, Roberts RC, Dougan G, Kingston RE, Modis Y, Lehner PJ Nat Genet. 2017 Jul;49(7):1035-1044. doi: 10.1038/ng.3878. Epub 2017 Jun 5. PMID:28581500[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Shao Y, Li Y, Zhang J, Liu D, Liu F, Zhao Y, Shen T, Li F. Involvement of histone deacetylation in MORC2-mediated down-regulation of carbonic anhydrase IX. Nucleic Acids Res. 2010 May;38(9):2813-24. doi: 10.1093/nar/gkq006. Epub 2010 Jan, 27. PMID:20110259 doi:http://dx.doi.org/10.1093/nar/gkq006
- ↑ Wang GL, Wang CY, Cai XZ, Chen W, Wang XH, Li F. Identification and expression analysis of a novel CW-type zinc finger protein MORC2 in cancer cells. Anat Rec (Hoboken). 2010 Jun;293(6):1002-9. doi: 10.1002/ar.21119. PMID:20225202 doi:http://dx.doi.org/10.1002/ar.21119
- ↑ Sanchez-Solana B, Li DQ, Kumar R. Cytosolic functions of MORC2 in lipogenesis and adipogenesis. Biochim Biophys Acta. 2014 Feb;1843(2):316-26. doi: 10.1016/j.bbamcr.2013.11.012., Epub 2013 Nov 25. PMID:24286864 doi:http://dx.doi.org/10.1016/j.bbamcr.2013.11.012
- ↑ Tchasovnikarova IA, Timms RT, Douse CH, Roberts RC, Dougan G, Kingston RE, Modis Y, Lehner PJ. Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2. Nat Genet. 2017 Jul;49(7):1035-1044. doi: 10.1038/ng.3878. Epub 2017 Jun 5. PMID:28581500 doi:http://dx.doi.org/10.1038/ng.3878
