Maternal DNMT3A-dependent de novo methylation of the paternal genome inhibits gene expression in the early embryo

Albert, Julien Richard; Yeung, Wan Kin Au; Toriyama, Keisuke; Kobayashi, Hisato; Hirasawa, Ryutaro; Brind’Amour, Julie; Bogutz, Aaron B.; Sasaki, Hidetada; Lorincz, Matthew C.

doi:10.1038/s41467-020-19279-7

Cited by 17 publications

(5 citation statements)

References 87 publications

(172 reference statements)

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“…Here we showed that the post-fertilization imprinted methylation we previously reported in mouse and human H19 ICRs also occurred in the mouse IG-DMR. Recently, whole-genome bisulfite sequencing analysis of a mouse pre-implantation embryo revealed that a number of genomic regions were de novo methylated on the paternal allele after fertilization [39]. Thus, post-fertilization DNA methylation that occurs against genome-wide reprogramming activity, may be an essential mechanism ensuring accurate gene expression in the early embryos.…”

Section: Discussionmentioning

confidence: 99%

The transgenic IG-DMR sequence of the mouse Dlk1-Dio3 domain acquired imprinted DNA methylation during the post-fertilization period

Matsuzaki

Sugihara

Tanimoto

2023

Epigenetics & Chromatin

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Background Allele-specific methylation of the imprinting control region (ICR) is the molecular basis for the genomic imprinting phenomenon that is unique to placental mammals. We previously showed that the ICR at the mouse H19 gene locus (H19 ICR) was unexpectedly established after fertilization and not during spermatogenesis in transgenic mice (TgM), and that the same activity was essential for the maintenance of paternal methylation of the H19 ICR at the endogenous locus in pre-implantation embryos. To examine the universality of post-fertilization imprinted methylation across animal species or imprinted loci, we generated TgM with two additional sequences. Results The rat H19 ICR, which is very similar in structure to the mouse H19 ICR, unexpectedly did not acquire imprinted methylation even after fertilization, suggesting a lack of essential sequences in the transgene fragment. In contrast, the mouse IG-DMR, the methylation of which is acquired during spermatogenesis at the endogenous locus, did not acquire methylation in the sperm of TgM, yet became highly methylated in blastocysts after fertilization, but only when the transgene was paternally inherited. Since these two sequences were evaluated at the same genomic site by employing the transgene co-placement strategy, it is likely that the phenotype reflects the intrinsic activity of these fragments rather than position-effect variegation. Conclusions Our results suggested that post-fertilization imprinted methylation is a versatile mechanism for protecting paternal imprinted methylation from reprogramming during the pre-implantation period.

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Section: Discussionmentioning

confidence: 99%

The transgenic IG-DMR sequence of the mouse Dlk1-Dio3 domain acquired imprinted DNA methylation during the post-fertilization period

Matsuzaki

Sugihara

Tanimoto

2023

Epigenetics & Chromatin

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“…We noted that the maternal genome in the control zygotes exhibited a slight methylation increase during the transition from oocyte to zygote. Despite the global loss of methylation in the zygotic pronuclei, de novo methylation has been observed in a subset of regions in the paternal genome, and it is believed that DNMT3A and DNMT1 are required for such de novo methylation [ 43 , 44 ]. DNMT3A was located in both parental pronuclei [ 44 ], implying that de novo methylation might also occur in the maternal genome.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the global loss of methylation in the zygotic pronuclei, de novo methylation has been observed in a subset of regions in the paternal genome, and it is believed that DNMT3A and DNMT1 are required for such de novo methylation [ 43 , 44 ]. DNMT3A was located in both parental pronuclei [ 44 ], implying that de novo methylation might also occur in the maternal genome. In this study, we found new methylated sites arising in the maternal genome after fertilization.…”

Section: Discussionmentioning

confidence: 99%

Early Expression of Tet1 and Tet2 in Mouse Zygotes Altered DNA Methylation Status and Affected Embryonic Development

Wang

Liu

et al. 2022

IJMS

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Ten-eleven translocation (Tet) dioxygenases can induce DNA demethylation by catalyzing 5-methylcytosine(5mC) to 5-hydroxymethylcytosine(5hmC), and play important roles during mammalian development. In mouse, Tet1 and Tet2 are not expressed in pronucleus-staged embryos and are not involved in the genomic demethylation of early zygotes. Here, we investigated the influence of Tet1 and Tet2 on methylation of parental genomes by ectopically expressing Tet1 and Tet2 in zygotes. Immunofluorescence staining showed a marked 5hmC increase in the maternal pronucleus after injection of Tet1 or Tet2 mRNA into zygotes. Whole-genome bisulfite sequencing further revealed that Tet2 greatly enhanced the global demethylation of both parental genomes, while Tet1 only promoted the paternal demethylation. Tet1 and Tet2 overexpression altered the DNA methylation across genomes, including various genic elements and germline-specific differently methylated regions. Tet2 exhibited overall stronger demethylation activity than Tet1. Either Tet1 or Tet2 overexpression impaired preimplantation embryonic development. These results demonstrated that early expression of Tet1 and Tet2 could substantially alter the zygotic methylation landscape and damage embryonic development. These findings provide new insights into understanding the function of Tet dioxygenases and the mechanism of DNA methylation in relation to embryogenesis.

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“…For example, several dozen CpG-rich promoters are de novo methylated by maternal DNMT3A on the paternal allele of the 2-cell embryo. Loss of maternal DNMT3A leads to a premature transcription of these paternally-expressed genes at the 4-cell stage 166 . In another study, the oocytes of hyperglycemic mice or from humans with diabetes, showed reduced expression of T et3 deoxygenase.…”

Section: Influence Of Sperm-inherited Epigenetic Factors On Embryonic...mentioning

confidence: 99%

Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development

Lismer

Kimmins

2023

Nat Commun

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Although more studies are demonstrating that a father’s environment can influence child health and disease, the molecular mechanisms underlying non-genetic inheritance remain unclear. It was previously thought that sperm exclusively contributed its genome to the egg. More recently, association studies have shown that various environmental exposures including poor diet, toxicants, and stress, perturbed epigenetic marks in sperm at important reproductive and developmental loci that were associated with offspring phenotypes. The molecular and cellular routes that underlie how epigenetic marks are transmitted at fertilization, to resist epigenetic reprogramming in the embryo, and drive phenotypic changes are only now beginning to be unraveled. Here, we provide an overview of the state of the field of intergenerational paternal epigenetic inheritance in mammals and present new insights into the relationship between embryo development and the three pillars of epigenetic inheritance: chromatin, DNA methylation, and non-coding RNAs. We evaluate compelling evidence of sperm-mediated transmission and retention of paternal epigenetic marks in the embryo. Using landmark examples, we discuss how sperm-inherited regions may escape reprogramming to impact development via mechanisms that implicate transcription factors, chromatin organization, and transposable elements. Finally, we link paternally transmitted epigenetic marks to functional changes in the pre- and post-implantation embryo. Understanding how sperm-inherited epigenetic factors influence embryo development will permit a greater understanding related to the developmental origins of health and disease.

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Maternal DNMT3A-dependent de novo methylation of the paternal genome inhibits gene expression in the early embryo

Cited by 17 publications

References 87 publications

The transgenic IG-DMR sequence of the mouse Dlk1-Dio3 domain acquired imprinted DNA methylation during the post-fertilization period

The transgenic IG-DMR sequence of the mouse Dlk1-Dio3 domain acquired imprinted DNA methylation during the post-fertilization period

Early Expression of Tet1 and Tet2 in Mouse Zygotes Altered DNA Methylation Status and Affected Embryonic Development

Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development

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