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.

Origin of cellular asymmetries in the pre-implantation mouse embryo: a hypothesis

“…The paternal genome in the male pronucleus undergoes rapid demethylation after fertilization, with DNA methylation being largely lost before the first mitosis. This active demethylation is mediated by Tet3, a dioxygenase that converts 5-methlycytosine to 5-hydroxymethlycytosine and which is present specifically in the male pronucleus [19]. By contrast, the maternal genome in the female pronucleus remains highly methylated until cleavage stages, when methylation is passively lost over the entire genome.…”

Diagnosis of abnormal human fertilization status based on pronuclear origin and/or centrosome number

“…Furthermore, a study of the DNA methylation pattern in human 3PN zygotes established that active demethylation of the paternal PN occurs post-fertilization in both c-IVF and ICSI [32]. In addition, recent studies have shown that the demethylation of paternal PN is induced by conversion from 5mC to 5hmC by ten-eleven translocation methylcytosine dioxygenases (TETs) [9][10][11]. Among TET proteins, TET3 is intensely expressed in oocytes and zygotes.…”

“…Recently, it was found that 5-methylcytosine (5mC) in the paternal genome is specifically converted to 5-hydroxymethylcytosine (5hmC) during the pronuclear stage [9][10][11]. Although these three studies were conducted in animals, we applied a similar approach in this study, using epigenetic divergence to determine the origin of mPN and fPN in abnormal human zygotes with 1PN and 3PN.…”

Propriétés et rôles biologiques des protéines TET au cours du développement et de l’hématopoïèse

“…Chez ces souris, la reprogrammation épigénétique du génome paternel est altérée. Les femelles dont l'allèle maternel est déficient pour Tet3 (Tet3 mat-/pat + ) ont une fécon-dité réduite, et leurs descendants décèdent avec des anomalies dans de multiples organes [23]. Il en est de même pour les souris double KO Tet1 -/-Tet2 -/-dont plus de la moitié meurent en période périnatale de troubles développementaux sévères.…”