2. Academic Validation
  3. MYC, mitochondrial metabolism and O-GlcNAcylation converge to modulate the activity and subcellular localization of DNA and RNA demethylases

MYC, mitochondrial metabolism and O-GlcNAcylation converge to modulate the activity and subcellular localization of DNA and RNA demethylases

  • Leukemia. 2022 Apr;36(4):1150-1159. doi: 10.1038/s41375-021-01489-7.
An-Ping Lin  # 1,  Zhijun Qiu  # 1,  Purushoth Ethiraj 1,  Binu Sasi 1,  Carine Jaafar 1,  Dinesh Rakheja 2,  Ricardo C T Aguiar 3 4
Affiliations

Affiliations

  • 1 Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX, 78229, USA.
  • 2 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 3 Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX, 78229, USA. aguiarr@uthscsa.edu.
  • 4 South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, TX, 78229, USA. aguiarr@uthscsa.edu.
  • # Contributed equally.
PMID: 34997181 DOI: 10.1038/s41375-021-01489-7
Abstract

Mitochondria can function as signaling organelles, and part of this output leads to epigenetic remodeling. The full extent of this far-reaching interplay remains undefined. Here, we show that MYC transcriptionally activates IDH2 and increases alpha-ketoglutarate (αKG) levels. This regulatory step induces the activity of αKG-dependent DNA hydroxylases and RNA demethylases, thus reducing global DNA and RNA methylation. MYC, in a IDH2-dependent manner, also promotes the nuclear accumulation of TET1-TET2-TET3, FTO and ALKBH5. Notably, this subcellular movement correlated with the ability of MYC, in an IDH2-dependent manner, and, unexpectedly, of αKG to directly induce O-GlcNAcylation. Concordantly, modulation of the activity of OGT and OGA, Enzymes that control the cycling of this non-canonical mono-glycosylation, largely recapitulated the effects of the MYC-IDH2-αKG axis on the subcellular movement of DNA and RNA demethylases. Together, we uncovered a hitherto unsuspected crosstalk between MYC, αKG and O-GlcNAcylation which could influence the epigenome and epitranscriptome homeostasis.

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