Discovery of the TET family of DNA methylcytosine oxidases

In collaboration with Dr. L. Aravind (NCBI), my lab made the paradigm-shifting observation that proteins of the TET family alter DNA methylation status by oxidising 5-methylcytosine (5mC) [C, D]. This discovery identified TET enzymes as the long-sought effectors of DNA demethylation, and called into question many previous studies of DNA methylation based on bisulfite sequencing (PMID 20126651). (a) We developed new methods for mapping 5hmC [17] and identified new regulators of TET activity [18]. (b) We showed that Tet1 and Tet2 have different functions in embryonic stem cells (PMID 24474761), and that TET proteins are essential regulators of embryonic development and pluripotency (PMID 21295276, 27930333 and unpublished). (c) In studies relevant to cancer, we showed that acute depletion of TET function in the mouse, by deletion of Tet2 and Tet3 in T cells, hematopoietic stem cells and several other cell types, results in skewed differentiation and the rapid, cell-intrinsic development of aggressive malignancies ([19, 20]; PMID: 21873190, 25510268, 27869616 and unpublished). Reviews on TET proteins and the relation of TET loss-of-function to cancer: PMID: 23698584, 25132561, 26595486. 17. Pastor WA*, Pape UJ*, Huang Y*, Henderson HR, Lister R, Ko MG, McLoughlin EM, Brudno Y, Maha-patra S, Kapranov P, Tahiliani M, Daley GQ, Liu XS, Ecker JR, Milos PM, Agarwal S, Rao A. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 2011, 473: 394-397. PMC3124347. 18. Ko M*, An J*, Bandukwala HS, Pastor WA, Segal MF, Li H, Koh KP, Hogan PG, Aravind L, Rao A. Modulation of TET2 expression and 5-methylcytosine oxidation by the Wnt inhibitor IDAX. Nature 2013; 497: 122-126. PMC3643997  19. An J, González-Avalos E, Chawla A, Jeong M, López-Moyado IF, Li W, Goodell MA, Chavez L, Ko M, Rao A. Acute loss of TET function results in aggressive myeloid cancer in mice. Nature Comm 2015, 6:10071. PMC4674670. 20. Tsagaratou A, González-Avalos E, Rautio S, Scott-Browne JP, Togher S, Pastor WA, Rothenberg EV, Chavez L, Lähdesmäki H, Rao A. TET proteins regulate lineage specification and TCR-mediated expan-sion of iNKT cells. Nature Immunology 2016; 18: 45-53.