@article{c2c52eff5eb7414e85ebe63f9fb0a209,
title = "MYC Regulation of D2HGDH and L2HGDH Influences the Epigenome and Epitranscriptome",
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",
author = "Qiu, {Zhi Jun} and Lin, {An Ping} and Shoulei Jiang and Elkashef, {Sara M.} and Jamie Myers and Subramanya Srikantan and Binu Sasi and Cao, {John Z.} and Godley, {Lucy A.} and Dinesh Rakheja and Yingli Lyu and Siyuan Zheng and Muniswamy Madesh and Yuzuru Shiio and Dahia, {Patricia L.M.} and Aguiar, {Ricardo C.T.}",
note = "Funding Information: We thank Dr. Dirk Eick for the P493-6 cells. Y.S. was supported by CA202485 (NCI), RP160487 and RP190385 (CPRIT), Owens Medical Research Foundation and UL1 TR001120 (NIH-CTSA). P.L.M.D. was supported by GM114102 (NIGMS), Alex's Lemonade Stand Foundation, and National Center for Advancing Translational Sciences (UL1 TR002645). M.M. is supported by the NIH and DOD (R01GM109882, R01HL086699, R01HL142673, DOD/DHP-CDMRP PR181598P-1). R.C.T.A. was supported by RP150277, RP170146, and RP190043 (CPRIT), TRP 6524-17 (Leukemia and Lymphoma Society), and I01BX001882 (VA Merit). FACS core is supported by P30 CA054174 (NCI). Z.Q. and A-P.L. designed, performed, and interpreted the assays. S.J. S.M.E. J.M. and B.S. performed the experiments. J.Z.C. and L.A.G. performed mass spectrometry measurements of DNA modifications. D.R. performed mass spectrometry measurements of metabolites. Y.L. and S.Z. designed and performed bioinformatics analysis. M.M. and S.S. contributed to the IF analysis. Y.S. contributed reagents and input in the study design. P.L.M.D. provided insights into the subcellular location studies. R.C.T.A. conceived the project, designed, performed and interpreted the assays, and wrote manuscript, which was reviewed by all authors. The authors declare no competing financial interests. Funding Information: We thank Dr. Dirk Eick for the P493-6 cells. Y.S. was supported by CA202485 ( NCI ), RP160487 and RP190385 (CPRIT), Owens Medical Research Foundation and UL1 TR001120 ( NIH -CTSA). P.L.M.D. was supported by GM114102 ( NIGMS ), Alex{\textquoteright}s Lemonade Stand Foundation , and National Center for Advancing Translational Sciences ( UL1 TR002645 ). M.M. is supported by the NIH and DOD ( R01GM109882 , R01HL086699 , R01HL142673 , DOD /DHP-CDMRP PR181598P-1). R.C.T.A. was supported by RP150277 , RP170146 , and RP190043 ( CPRIT ), TRP 6524-17 ( Leukemia and Lymphoma Society ), and I01BX001882 ( VA Merit ). FACS core is supported by P30 CA054174 ( NCI ). Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd",
year = "2020",
month = may,
day = "21",
doi = "10.1016/j.chembiol.2020.02.002",
language = "English (US)",
volume = "27",
pages = "538--550.e7",
journal = "Cell Chemical Biology",
issn = "2451-9456",
publisher = "Elsevier Inc.",
number = "5",
}