Epigenetic regulation and transcriptional repression by Tet1 in the early post-implantation mouse embryo: Methylation data.

The mammalian TET dioxygenases contribute to global waves of DNA demethylation in the zygote and in primordial germ cells, but their involvement during de novo DNA methylation at peri/post-implantation development is unknown. Here, we show novel physiological functions of Tet1 in the pre-primitive streak stage mouse embryo, where it is expressed not only in the primed-state epiblast, but also in the extra-embryonic ectoderm. In the epiblast, Tet1 contributes to DNA methylation patterning, which indirectly results in dominant transcriptional repression involving a Jumonji-family gene Jmjd8. In the extra-embryonic ectoderm, Tet1 suppresses expression of metabolic genes involved in oxidative phosphorylation. These lineage-specific gene repressive functions, involving distinct modes of regulation by DNA methylation, counteract precocious differentiation of the embryo prior to the onset of gastrulation. Such dysregulation in the absence of Tet1 are surprisingly tolerated in an inbred strain but results in full embryonic lethality in non-inbred mice, thus implicating a complex but essential role of Tet1 in normal gestational development.