Abstract

The Ten-Eleven-Translocation (TET) enzymes catalyze DNA demethylation by reiterative oxidation of 5-methylcytosine. While their catalytic functions in development and disease are well studied, their physiological roles following implantation of the mammalian embryo remain unclear. Notably, Tet1-deficient mice show strain-differences in the rates of embryonic lethality, which is highly penetrant in mixed background and outbred stocks, but unusually reduced in the C57BL /6 congenic strain. My recent work suggests that these phenotypes are the result of an unexpected role for TET1 to suppress precocious differentiation of the epiblast and extraembryonic ectoderm prior to gastrulation. A complex interplay of TET1 ’s catalytic and non-catalytic activities is critical for proper neural tube closure at post-gastrulation. Moreover, the catalytic effects of TET1 on the epiblast DNA methylome may provide an epigenetic safeguard against diseases related to aging, neurodegeneration and cancer later in life. Finally, I will describe an intriguing non-coding function of the TET1 gene in pluripotency state transitions during epigenetic reprogramming.

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