Sperm and eggs carry distinctive epigenetic modifications that are adjusted by reprogramming following fertilization. The paternal genome undergoes active DNA demethylation before the first mitotic division. The biological significance and mechanisms of paternal epigenome remodeling have remained unclear. We find that, within mouse zygotes, oxidation of occurs in the paternal genome, changing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). In Tet3 oxidase-deficient zygotes from conditional knockout mice, the conversion of 5mC into 5hmC fails to occur. Thus, the loss of 5mC in the paternal genome in zygotes is caused by its conversion to 5hmC mediated by Tet3. Deficiency of Tet3 also impedes demethylation at the paternal copy of genes such as Oct4 and Nanog  and delays the subsequent reactivation of Oct4 in early embryos. Heterozygous mutant embryos lacking maternal Tet3 suffer increased developmental failures, with female mice depleted of Tet3 in the germ line displaying severely reduced fecundity. Importantly, oocytes lacking Tet3 also show impaired reprogramming of injected somatic cell nuclei. We conclude that Tet3-mediated DNA oxidation is essential for epigenetic reprogramming in the early embryo following natural fertilization, as well as for the reprogramming of somatic cell nuclei during animal cloning.

DNA oxidation towards totipotency in mammalian development

244th National Meeting (2012)

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