DNA methylation modulates nucleosome retention in sperm and H3K4 methylation deposition in early mouse embryos

Grigorios Fanourgakis, Laura Gaspa-Toneu, Pavel A. Komarov, Panagiotis Papasaikas, Evgeniy A. Ozonov, Sebastien A. Smallwood and Antoine H. F. M. Peters ()
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Grigorios Fanourgakis: Friedrich Miescher Institute for Biomedical Research
Laura Gaspa-Toneu: Friedrich Miescher Institute for Biomedical Research
Pavel A. Komarov: Friedrich Miescher Institute for Biomedical Research
Panagiotis Papasaikas: Friedrich Miescher Institute for Biomedical Research
Evgeniy A. Ozonov: Friedrich Miescher Institute for Biomedical Research
Sebastien A. Smallwood: Friedrich Miescher Institute for Biomedical Research
Antoine H. F. M. Peters: Friedrich Miescher Institute for Biomedical Research

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract In the germ line and during early embryogenesis, DNA methylation (DNAme) undergoes global erasure and re-establishment to support germ cell and embryonic development. While DNAme acquisition during male germ cell development is essential for setting genomic DNA methylation imprints, other intergenerational roles for paternal DNAme in defining embryonic chromatin are unknown. Through conditional gene deletion of the de novo DNA methyltransferases Dnmt3a and/or Dnmt3b, we observe that DNMT3A primarily safeguards against DNA hypomethylation in undifferentiated spermatogonia, while DNMT3B catalyzes de novo DNAme during spermatogonial differentiation. Failing de novo DNAme in Dnmt3a/Dnmt3b double deficient spermatogonia is associated with increased nucleosome occupancy in mature sperm, preferentially at sites with higher CpG content, supporting the model that DNAme modulates nucleosome retention in sperm. To assess the impact of altered sperm chromatin in formatting embryonic chromatin, we measure H3K4me3 occupancy at paternal and maternal alleles in 2-cell embryos using a transposon-based tagging approach. Our data show that reduced DNAme in sperm renders paternal alleles permissive for H3K4me3 establishment in early embryos, independently of possible paternal inheritance of sperm born H3K4me3. Together, this study provides evidence that paternally inherited DNAme directs chromatin formation during early embryonic development.

Date: 2025
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DOI: 10.1038/s41467-024-55441-1

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