MYC Regulation of D2HGDH and L2HGDH Influences the Epigenome and Epitranscriptome

Zhi Jun Qiu, An Ping Lin, Shoulei Jiang, Sara M. Elkashef, Jamie Myers, Subramanya Srikantan, Binu Sasi, John Z. Cao, Lucy A. Godley, Dinesh Rakheja, Yingli Lyu, Siyuan Zheng, Muniswamy Madesh, Yuzuru Shiio, Patricia L.M. Dahia, Ricardo C.T. Aguiar

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)538-550.e7
JournalCell Chemical Biology
Volume27
Issue number5
DOIs
StatePublished - May 21 2020

Keywords

  • 2-hydroxyglutarate
  • DNA methylation
  • MYC
  • RNA methylation
  • alpha-ketoglutarate
  • dioxygenases
  • enhancer
  • lymphoma
  • metabolites
  • super-enhancer

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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  • Cite this

    Qiu, Z. J., Lin, A. P., Jiang, S., Elkashef, S. M., Myers, J., Srikantan, S., Sasi, B., Cao, J. Z., Godley, L. A., Rakheja, D., Lyu, Y., Zheng, S., Madesh, M., Shiio, Y., Dahia, P. L. M., & Aguiar, R. C. T. (2020). MYC Regulation of D2HGDH and L2HGDH Influences the Epigenome and Epitranscriptome. Cell Chemical Biology, 27(5), 538-550.e7. https://doi.org/10.1016/j.chembiol.2020.02.002