The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes
The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes
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Tet3 DNA 双加氧酶在卵母细胞表观遗传重编程中的作用
DOI：
10.1038/nature10443
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发表时间：
2011-09-29
期刊：
影响因子：
64.8
通讯作者：
Xu, Guo-Liang
中科院分区：
文献类型：
--
作者：
Gu, Tian-Peng;Guo, Fan;Xu, Guo-Liang
精子和卵子携带独特的表观遗传修饰，在受精后通过重新编程进行调整。合子的父系基因组在第一次有丝分裂前经历活跃的DNA去甲基化。这种父系表观基因组重塑的生物学意义和机制尚不清楚。在这里，我们报道，在小鼠受精卵中，5-甲基胞嘧啶（5mC）的氧化发生在父系基因组上，将5mC转变为5-羟甲基胞嘧啶（5hmC）。此外，我们证明了双加氧酶Tet3 （ref.）在雄性原核中特异性富集。在条件敲除小鼠的tet3缺陷合子中，5mC在父系基因组中转化为5hmC的过程失败，5mC的水平保持不变。Tet3的缺乏也阻碍了父本oct4和nanoggenes的去甲基化过程，并延迟了早期胚胎中父本衍生的doct4转基因的随后激活。生殖系中缺乏Tet3的雌性小鼠生殖力严重下降，其杂合突变后代缺乏母体Tet3，发育失败的发生率增加。缺乏Tet3的卵母细胞似乎也降低了从体细胞中重新编程注入细胞核的能力。因此，tet3介导的DNA羟基化参与了自然受精后合子父本DNA的表观遗传重编程，也可能有助于动物克隆过程中的体细胞核重编程。
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. ) 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 paternalOct4andNanoggenes and delays the subsequent activation of a paternally derivedOct4transgene 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.