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TRANSCRIPTIONAL CONTROL AND SIGNAL TRANSDUCTION, CELL CYCLE

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

Leukemia volume 36, pages 1150–1159 (2022)Cite this article

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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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Fig. 1: IDH2 is a transcriptional target of MYC.
Fig. 2: MYC-IDH2-αKG axis, DNA/RNA methylation and demethylase activity.
Fig. 3: Intermediate metabolites modulate MYC-IDH2 effects on DNA and RNA methylation.
Fig. 4: Control of the subcellular localization of TET1-3, FTO and ALKBH5 by the MYC-IDH2 and MYC-D2HGDH/L2HGDH interplays.
Fig. 5: O-GlcNAcylation and the modulation of TET enzymes and RNA demethylases FTO and ALKBH5.

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Acknowledgements

This work was funded by grants from the National Institute of Health (R01-ES031522 and R01-GM140456), the Cancer Prevention and Research Institute of Texas (CPRIT - RP190043) and the Veterans Administration (I01BX001882), all to RCTA. We thank Jamie Myers for technical help.

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  1. These authors contributed equally: An-Ping Lin, Zhijun Qiu.

Authors and Affiliations

  1. Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX, 78229, USA

    An-Ping Lin, Zhijun Qiu, Purushoth Ethiraj, Binu Sasi, Carine Jaafar & Ricardo C. T. Aguiar

  2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Dinesh Rakheja

  3. South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, TX, 78229, USA

    Ricardo C. T. Aguiar

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Contributions

A-PL and ZQ designed, performed, and interpreted the assays; PE, CJ and BS performed experiments; DR performed mass spectrometry measurements of metabolites. RCTA conceived the project, designed, and interpreted the assays, wrote manuscript, which was reviewed by all authors.

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Correspondence to Ricardo C. T. Aguiar.

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Lin, AP., Qiu, Z., Ethiraj, P. et al. MYC, mitochondrial metabolism and O-GlcNAcylation converge to modulate the activity and subcellular localization of DNA and RNA demethylases. Leukemia 36, 1150–1159 (2022). https://doi.org/10.1038/s41375-021-01489-7

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