A Big Surprise in the Little Zygote: The Curious Business of Losing Methylated Cytosines

Gkountela, Sofia; Clark, Amander T.

doi:10.1016/j.stem.2014.09.005

Cited by 13 publications

(9 citation statements)

References 10 publications

(14 reference statements)

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“…Interestingly, a recent study suggested that 5mCs within certain genomic loci are converted to unmodified cytosines in mouse zygotes in a Tet3-dependent but thymine DNA glycosylase (TDG)-independent manner, implying the existence of an undefined demethylation pathway (Guo et al, 2014a). To reveal such a mechanism, a hypothesis-driven candidate approach will be required because genome-wide screening is difficult to perform in zygotes (Gkountela and Clark, 2014). However, there may be many candidate factors, including deaminases, base excision repair enzymes, decarboxylases, and the elongator, that could be involved in active DNA demethylation (Messerschmidt et al, 2014;Wu and Zhang, 2014;Wu and Zhang, 2010).…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency, but Not Defective Paternal 5mC Oxidation, Accounts for the Developmental Defects of Maternal Tet3 Knockouts

Inoue¹,

Shen²,

Matoba³

et al. 2015

Cell Reports

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Paternal DNA demethylation in mammalian zygotes is achieved through Tet3-mediated iterative oxidation of 5-methylcytosine (5mC) coupled with replication-dependent dilution. Tet3-mediated paternal DNA demethylation is believed to play important roles in mouse development given that Tet3 heterozygous embryos derived from Tet3-deficient oocytes exhibit embryonic sublethality. Here, we demonstrate that the sublethality phenotype of the Tet3 maternal knockout mice is caused by haploinsufficiency but not defective paternal 5mC oxidation. We found that Tet3 heterozygous progenies derived from heterozygous father or mother also exhibit sublethality. Importantly, wild-type embryos reconstituted with paternal pronuclei that bypassed 5mC oxidation develop and grow to adulthood normally. Genome-scale DNA methylation analysis demonstrated that hypermethylation in maternal Tet3 knockout embryos is largely diminished by the blastocyst stage. Our study thus reveals that Tet3-mediated paternal 5mC oxidation is dispensable for mouse development and suggests the existence of a compensatory mechanism for defective 5mC oxidation in preimplantation embryos.

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Section: Discussionmentioning

confidence: 99%

Haploinsufficiency, but Not Defective Paternal 5mC Oxidation, Accounts for the Developmental Defects of Maternal Tet3 Knockouts

Inoue¹,

Shen²,

Matoba³

et al. 2015

Cell Reports

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“…However, recently published studies stated that DNA replication is the main contributor to DNA demethylation of the paternal genome [Guo et al, 2014;Shen et al, 2014], and Tet3-dependent DNA demethylation also occurs on the maternal genome in zygotes before the first mitotic division [Shen et al, 2014;Wang et al, 2014]. Overall, these 3 studies demonstrated that 5mC can be removed from the zygotic genome by 3 processes: Tetmediated active demethylation, replication-dependent demethylation, or replication-dependent removal of 5hmC after oxidation [Gkountela and Clark, 2014]. On the other hand, a new study published in 2016 concluded that Tet3 and the formation of 5hmC is not needed for the initial loss of 5mC in the paternal genome [Amouroux et al, 2016].…”

Section: Discussionmentioning

confidence: 95%

Superovulation Influences Methylation Reprogramming and Delays Onset of DNA Replication in Both Pronuclei of Mouse Zygotes

Diken¹,

Linke²,

Baumgart³

et al. 2018

Cytogenet Genome Res

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Although an essential component of assisted reproductive technologies, ovarian stimulation, or superovulation, may interfere with the epigenetic reprogramming machinery during early embryogenesis and gametogenesis. To investigate the possible impact of superovulation particularly on the methylation reprogramming process directly after fertilization, we performed immunofluorescence staining of pronuclear (PN) stage embryos with antibodies against 5mC and 5hmC. PN stage embryos obtained by superovulation displayed an increased incidence of abnormal methylation and hydroxymethylation patterns in both maternal and paternal pronuclear DNA. Subsequent single-cell RT-qPCR analyses of the Tet1, Tet2, and Tet3 genes revealed no significant expression differences between PN stage embryos from spontaneously and superovulated matings that could be causative for the abnormal methylation and hydroxymethylation patterns. To analyze the possible contribution of TET-independent replication-associated demethylation mechanisms, we then determined the 5mC and 5hmC levels of PN stage mouse embryos using immunofluorescence analyses after inhibition of DNA replication with aphidicolin. Inhibition of DNA replication had no effect on abnormal methylation and hydroxymethylation patterns that still persisted in the superovulated group. Interestingly, the onset of DNA replication, which was also analyzed in these experiments, was remarkably delayed in the superovulated group. Our findings imply an impact of superovulation on both replication-dependent and -independent or yet unknown demethylation mechanisms in PN stage mouse embryos. In addition, they reveal for the first time a negative effect of superovulation on the initiation of DNA replication in PN stage mouse embryos.

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“…Until recently, it was widely accepted that the maternal genome and paternal genome were not actively demethylated or passively demethylated, respectively. It should be noted, however, that active and passive demethylation do not occur exclusively on the paternal and maternal genomes, as it has been demonstrated that both genomes undergo widespread active and passive demethylation in the zygote prior to the first mitotic division (Gkountela & Clark 2014, Guo et al 2014a.…”

Section: Epigenetic Reprogramming During Sperm Developmentmentioning

confidence: 99%

Epigenetic reprogramming during spermatogenesis and male factor infertility

McSwiggin¹,

O’Doherty²

2018

Reproduction

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Infertility is an often devastating diagnosis encountered by around one in six couples who are trying to conceive. Moving away from the long-held belief that infertility is primarily a female issue, it is now recognised that half, if not more, of these cases may be due to male factors. Recent evidence has suggested that epigenetic abnormalities in chromatin dynamics, DNA methylation or sperm-borne RNAs may contribute to male infertility. In light of advances in deep sequencing technologies, researchers have been able to increase the coverage and depth of sequencing results, which in turn has allowed more comprehensive analyses of spermatozoa chromatin dynamics and methylomes and enabled the discovery of new subsets of sperm RNAs. This review examines the most current literature related to epigenetic processes in the male germline and the associations of aberrant modifications with fertility and development.

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A Big Surprise in the Little Zygote: The Curious Business of Losing Methylated Cytosines

Cited by 13 publications

References 10 publications

Haploinsufficiency, but Not Defective Paternal 5mC Oxidation, Accounts for the Developmental Defects of Maternal Tet3 Knockouts

Haploinsufficiency, but Not Defective Paternal 5mC Oxidation, Accounts for the Developmental Defects of Maternal Tet3 Knockouts

Superovulation Influences Methylation Reprogramming and Delays Onset of DNA Replication in Both Pronuclei of Mouse Zygotes

Epigenetic reprogramming during spermatogenesis and male factor infertility

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