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Cell Chem Biol. 2020 Feb 24. pii: S2451-9456(20)30040-4. doi: 10.1016/j.chembiol.2020.02.002. [Epub ahead of print]

MYC Regulation of D2HGDH and L2HGDH Influences the Epigenome and Epitranscriptome.

Author information

1
Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.
2
Division of Nephrology, Center for Renal Precision Medicine, Department of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.
3
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
4
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5
Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.
6
Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA; Department of Epidemiology and Biostatistics, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.
7
Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA; Department of Biochemistry, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.
8
Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA; South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, TX 78229, USA. Electronic address: aguiarr@uthscsa.edu.

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.

KEYWORDS:

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

Conflict of interest statement

Declaration of Interests The authors declare no competing financial interests.

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