DNA oxidation towards totipotency in mammalian development Guoliang Xu Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai Mammalian development starts with the fertilization of sperm and eggs that carry distinctive epigenetic modifications that are adjusted through chromatin remodeling. The paternal genome in the zygote undergoes active DNA demethylation before the first mitotic cell division. The biological significance and mechanisms of this early epigenome remodeling have remained unclear. We find that, within mouse zygotes, DNA oxidation of occurs on the paternal genome, changing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and 5-carboxylcytosine (5caC). In Tet3-deficient zygotes from conditional knockout mice, the oxidation of 5mC fails to occur. Thus, the loss of 5mC in the paternal genome in developing zygotes is caused by Tet3-mediated oxidation. Deficiency of Tet3 impedes demethylation at the paternal Oct4 and Nanog genes and delays their subsequent reactivation in early embryos. Heterozygous mutant embryos derived from occytes lacking the maternal Tet3 suffer increased developmental failures, with female mice depleted of Tet3 in the germ line displaying severely reduced fecundity. Importantly, oocytes lacking Tet3 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, and also for the reprogramming of somatic cell nuclei during animal cloning.

DNA oxidation towards totipotency in mammalian development

Guoliang Xu

Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai

Mammalian development starts with the fertilization of sperm and eggs that carry distinctive epigenetic modifications that are adjusted through chromatin remodeling. The paternal genome in the zygote undergoes active DNA demethylation before the first mitotic cell division. The biological significance and mechanisms of this early epigenome remodeling have remained unclear. We find that, within mouse zygotes, DNA oxidation of occurs on the paternal genome, changing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and 5-carboxylcytosine (5caC). In Tet3-deficient zygotes from conditional knockout mice, the oxidation of 5mC fails to occur. Thus, the loss of 5mC in the paternal genome in developing zygotes is caused by Tet3-mediated oxidation. Deficiency of Tet3 impedes demethylation at the paternal Oct4 and Nanog genes and delays their subsequent reactivation in early embryos. Heterozygous mutant embryos derived from occytes lacking the maternal Tet3 suffer increased developmental failures, with female mice depleted of Tet3 in the germ line displaying severely reduced fecundity. Importantly, oocytes lacking Tet3 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, and also for the reprogramming of somatic cell nuclei during animal cloning.