MYC Regulation of D2HGDH and L2HGDH Influences the Epigenome and Epitranscriptome

Cell Chem Biol. 2020 May 21;27(5):538-550.e7. doi: 10.1016/j.chembiol.2020.02.002. Epub 2020 Feb 25.


Mitochondrial D2HGDH and L2HGDH catalyze the oxidation of D-2-HG and L-2-HG, respectively, into αKG. This contributes to cellular homeostasis in part by modulating the activity of αKG-dependent dioxygenases. Signals that control the expression/activity of D2HGDH/L2HGDH are presumed to broadly influence physiology and pathology. Using cell and mouse models, we discovered that MYC directly induces D2HGDH and L2HGDH transcription. Furthermore, in a manner suggestive of D2HGDH, L2HGDH, and αKG dependency, MYC activates TET enzymes and RNA demethylases, and promotes their nuclear localization. Consistent with these observations, in primary B cell lymphomas MYC expression positively correlated with enhancer hypomethylation and overexpression of lymphomagenic genes. Together, these data provide additional evidence for the role of mitochondria metabolism in influencing the epigenome and epitranscriptome, and imply that in specific contexts wild-type TET enzymes could demethylate and activate oncogenic enhancers.

Keywords: 2-hydroxyglutarate; DNA methylation; MYC; RNA methylation; alpha-ketoglutarate; dioxygenases; enhancer; lymphoma; metabolites; super-enhancer.

Publication types

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

MeSH terms

  • Alcohol Oxidoreductases / genetics*
  • Animals
  • Cell Line
  • Epigenome*
  • Female
  • Humans
  • Lymphoma, B-Cell / genetics*
  • Male
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins c-myc / genetics*
  • Transcriptional Activation*
  • Transcriptome
  • Tumor Cells, Cultured


  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Alcohol Oxidoreductases
  • D2HGDH protein, human
  • L2HGDH protein, human