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TET methylcytosine oxidases: new insights from a decade of research

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Abstract

In mammals, DNA methyltransferases transfer a methyl group from S-adenosylmethionine to the 5 position of cytosine in DNA. The product of this reaction, 5-methylcytosine (5mC), has many roles, particularly in suppressing transposable and repeat elements in DNA. Moreover, in many cellular systems, cell lineage specification is accompanied by DNA demethylation at the promoters of genes expressed at high levels in the differentiated cells. However, since direct cleavage of the C-C bond connecting the methyl group to the 5 position of cytosine is thermodynamically disfavoured, the question of whether DNA methylation was reversible remained unclear for many decades. This puzzle was solved by our discovery of the TET (Ten-Eleven Translocation) family of 5-methylcytosine oxidases, which use reduced iron, molecular oxygen and the tricarboxylic acid cycle metabolite 2-oxoglutarate (also known as α-ketoglutarate) to oxidise the methyl group of 5mC to 5-hydroxymethylcytosine (5hmC) and beyond. TET-generated oxidised methylcytosines are intermediates in at least two pathways of DNA demethylation, which differ in their dependence on DNA replication. In the decade since their discovery, TET enzymes have been shown to have important roles in embryonic development, cell lineage specification, neuronal function and cancer. We review these findings and discuss their implications here.

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Acknowledgments

The authors thank all current and previous Rao lab members for their work on published papers cited in this review, and for their inputs and many stimulating discussions over the years. We also thank the Flow Cytometry and Functional Genomics cores at the La Jolla Institute for Immunology for cell sorting and next-generation sequencing. This work was supported by National Institutes of Health (NIH) Grants R01 AI128589 and R35 CA210043 (to A.R). C.W.L. was supported by the Independent Investigator Fund (La Jolla Institute/Kyowa Kirin) and the Irvington Postdoctoral Fellowship from the Cancer Research Institute. I.F.L.-M. was supported by a University of California Institute for Mexico and the United States–Consejo Nacional de Ciencia y Tecnología Fellowship. L.A. is supported by the intramural funds of the National Library of Medicine, NIH, USA. M.T. was supported by the Packard Fellowship for Science and Engineering. Funding for Illumina HiSeq 2500 and BD FACSAria II is supported by NIH (NIH S10OD016262 and NIH S10RR027366).

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA

    Chan-Wang J. Lio, Xiaojing Yue, Isaac F. López-Moyado & Anjana Rao

  2. Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, 92093, USA

    Isaac F. López-Moyado & Anjana Rao

  3. Sanford Consortium for Regenerative Medicine, La Jolla, CA, 92093, USA

    Isaac F. López-Moyado & Anjana Rao

  4. Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, 10012, USA

    Mamta Tahiliani

  5. Department of Biology, New York University, New York, NY, 10003, USA

    Mamta Tahiliani

  6. National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, 20892, USA

    L. Aravind

  7. Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA

    Anjana Rao

  8. Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA

    Anjana Rao

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  1. Chan-Wang J. Lio
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  2. Xiaojing Yue
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  3. Isaac F. López-Moyado
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  4. Mamta Tahiliani
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  5. L. Aravind
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  6. Anjana Rao
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Corresponding author

Correspondence to Anjana Rao.

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AR is on the scientific advisory board of Cambridge Epigenetix (Cambridge, UK). The other authors declare no competing interests.

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This article is part of the Topical Collection: Chromatin Biology and Epigenetics.

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Lio, CW.J., Yue, X., López-Moyado, I.F. et al. TET methylcytosine oxidases: new insights from a decade of research. J Biosci 45, 21 (2020). https://doi.org/10.1007/s12038-019-9973-4

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  • DOI: https://doi.org/10.1007/s12038-019-9973-4

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