Beyond Cytosine Methylation: Ten-Eleven Translocation Proteins, Oxidized Methylcytosines, and Cancer

We discovered some years ago that enzymes of the TET (Ten-Eleven Translocation) family were a new class of epigenetic regulators that altered the modification status of cytosine bases in DNA. The three mammalian TET enzymes - TET1, TET2 and TET3 - successively oxidize the methyl group of 5-methylcytosine (5mC) to yield 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). These modified cytosine bases (together termed oxidized methylcytosines, oxi-mC) facilitate DNA demethylation and are also novel epigenetic marks. DNA methylation has long been linked to developmental processes and to oncogenesis; similarly TET proteins, which alter DNA modification status, are implicated in numerous biological processes, including cell lineage specification, embryonic development, neuronal function, somatic cell reprogramming and cancer. Loss-of-function mutations in the TET2 gene are frequently associated with lymphoid and myeloid cancers in humans. Using mouse models and biochemical and genome-wude approaches, we have analysed the role of TET proteins and oxi-mC in immune and haematopoietic cells. I will describe the data and discuss possible mechanisms.