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

Proc Natl Acad Sci U S A. 2019 Jun 25;116(26):12851-12856. doi: 10.1073/pnas.1817662116. Epub 2019 Jun 10.


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.

Keywords: 2-hydroxyglutarate; differentiation; isocitrate dehydrogenase; myogenesis; sarcoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Line
  • Chromatin Assembly and Disassembly
  • DNA Methylation
  • Glutarates / metabolism*
  • Glutarates / pharmacology
  • Histones / metabolism*
  • Isocitrate Dehydrogenase / genetics
  • Mice
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / drug effects
  • Mouse Embryonic Stem Cells / metabolism
  • Muscle Fibers, Skeletal / cytology
  • Muscle Fibers, Skeletal / metabolism
  • Mutation
  • MyoD Protein / metabolism*


  • Glutarates
  • Histones
  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • alpha-hydroxyglutarate
  • Isocitrate Dehydrogenase
  • Idh1 protein, mouse