title: The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes.
abstract: Sperm and eggs carry distinctive epigenetic modifications that are adjusted by reprogramming after fertilization. The paternal genome in a zygote undergoes active DNA demethylation before the first mitosis. The biological significance and mechanisms of this paternal epigenome remodelling have remained unclear. 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.
authors: Group of DNA Metabolism, The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Tian-Peng
authors: TP
authors: Gu
authors: Fan
authors: F
authors: Guo
authors: Hui
authors: H
authors: Yang
authors: Hai-Ping
authors: HP
authors: Wu
authors: Gui-Fang
authors: GF
authors: Xu
authors: Wei
authors: W
authors: Liu
authors: Zhi-Guo
authors: ZG
authors: Xie
authors: Linyu
authors: L
authors: Shi
authors: Xinyi
authors: X
authors: He
authors: Seung-gi
authors: SG
authors: Jin
authors: Khursheed
authors: K
authors: Iqbal
authors: Yujiang Geno
authors: YG
authors: Shi
authors: Zixin
authors: Z
authors: Deng
authors: Piroska E
authors: PE
authors: Szabó
authors: Gerd P
authors: GP
authors: Pfeifer
authors: Jinsong
authors: J
authors: Li
authors: Guo-Liang
authors: GL
authors: Xu
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D000483:Alleles; D000818:Animals; D065150:Cellular Reprogramming; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D047108:Embryonic Development; D044127:Epigenesis, Genetic; D005260:Female; D005298:Fertility / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D009865:Oocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism*; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015053:Zygote / Q000166:cytology / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D004247:DNA; D049308:Dioxygenases; C551915:Tet3 protein, mouse