2-hydroxyglutarate inhibits MyoD-mediated differentiation by preventing H3K9 demethylation Journal Article

   

Authors:	Schvartzman, J. M.; Reuter, V. P.; Koche, R. P.; Thompson, C. B.
Article Title:	2-hydroxyglutarate inhibits MyoD-mediated differentiation by preventing H3K9 demethylation
Abstract:	Oncogenic IDH1/2 mutations produce 2-hydroxyglutarate (2HG), resulting in competitive inhibition of DNA and protein demethylation. IDH-mutant cancer cells show an inability to differentiate but whether 2HG accumulation is sufficient to perturb differentiation directed by lineage-specifying transcription factors is unknown. A MyoD-driven model was used to study the role of IDH mutations in the differentiation of mesenchymal cells. The presence of 2HG produced by oncogenic IDH2 blocks the ability of MyoD to drive differentiation into myotubes. DNA 5mC hypermethylation is dispensable while H3K9 hypermethylation is required for this differentiation block. IDH2-R172K mutation results in H3K9 hypermethylation and impaired accessibility at myogenic chromatin regions but does not result in genome-wide decrease in accessibility. The results demonstrate the ability of the oncometabolite 2HG to block transcription factor-mediated differentiation in a molecularly defined system. © 2019 National Academy of Sciences. All rights reserved.
Keywords:	sarcoma; differentiation; isocitrate dehydrogenase; myogenesis; 2-hydroxyglutarate
Journal Title:	Proceedings of the National Academy of Sciences of the United States of America
Volume:	116
Issue:	26
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Date Published:	2019-06-25
Start Page:	12851
End Page:	12856
Language:	English
DOI:	10.1073/pnas.1817662116
PUBMED:	31182575
PROVIDER:	scopus
PMCID:	PMC6600935
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85068159401&doi=10.1073%2fpnas.1817662116&partnerID=40&md5=34d34ad85cf129115a099d5f8be2df6b
Notes:	Article -- Source: Scopus

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