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

Authors: Lin, An-Ping; Qiu, Zhijun; Ethiraj, Purushoth; Sasi, Binu; Jaafar, Carine; Rakheja, Dinesh; Aguiar, Ricardo C T

Published In Leukemia, (2022 Apr)

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.

PubMed ID: 34997181

MeSH Terms: Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism; DNA Methylation*; DNA-Binding Proteins/metabolism; DNA/metabolism; Humans; Mitochondria/metabolism; Mixed Function Oxygenases/genetics; Mixed Function Oxygenases/metabolism; Proto-Oncogene Proteins/metabolism; RNA*