Sperm and eggs carry distinctive epigenetic modifications that are adjusted by reprogramming after fertilization1. The paternal genome in a zygote undergoes active DNA demethylation before the first mitosis2,3. The biological significance and mechanisms of this paternal epigenome remodelling have remained unclear4. Here we report that, within mouse zygotes, oxidation of 5-methylcytosine (5mC) occurs on the paternal genome, changing 5mC into 5-hydroxymethylcytosine (5hmC). Furthermore, we demonstrate that the dioxygenase Tet3 (ref. 5) is enriched specifically in the male pronucleus. In Tet3-deficient zygotes from conditional knockout mice, paternal-genome conversion of 5mC into 5hmC fails to occur and the level of 5mC remains constant. Deficiency of Tet3 also impedes the demethylation process of the paternal Oct4 and Nanog genes and delays the subsequent activation of a paternally derived Oct4 transgene in early embryos. Female mice depleted of Tet3 in the germ line show severely reduced fecundity and their heterozygous mutant offspring lacking maternal Tet3 suffer an increased incidence of developmental failure. Oocytes lacking Tet3 also seem to have a reduced ability to reprogram the injected nuclei from somatic cells. Therefore, Tet3-mediated DNA hydroxylation is involved in epigenetic reprogramming of the zygotic paternal DNA following natural fertilization and may also contribute to somatic cell nuclear reprogramming during animal cloning.
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We thank C. Walsh and M. Rots for critical reading of the manuscript, J. Walter for discussions, H. Qi for providing cDNA of mouse oocytes, R. Zhang & Q. Cui for Tet3 cDNA, L. Li for help with 5hmCMP synthesis, Shanghai Research Center for Model Organisms for blastocyst injection, and J. Gao for mouse work. This study was supported by grants from the Ministry of Science and Technology China (2007CB947503 to G.-L.X., 2007CB947101 to J.L., and 2009CB941101 to G.-L.X. and J.L.), National Science Foundation of China (30730059 to G.-L.X. and 30871430 to J.L.), the Chinese Academy of Sciences (XDA01010301 to G.-L.X.; XDA01010403 and KSCX2-YW-R-110 to J.L.) and the NIH (GM078458 to Y.G.S.).
The file contains Supplementary Figures 1-16 with legends, Supplementary Tables 1-6 and additional references.
About this article
Functions of intrinsic disorder in proteins involved in DNA demethylation during pre-implantation embryonic development
International Journal of Biological Macromolecules (2019)