While stories of Mom meeting Dad often leave their mark on a family, and sometimes a nation, the plot has now thickened thanks to new findings showing that Mom’s DNMT3A leaves its mark on Dad’s genome in the early embryo.
DNA methylation in the male germline undergoes massive changes during preimplantation. High paternal DNA methylation levels are progressively reduced with each DNA replication cycle in the fertilized zygote. An exception to this is CpG islands, which remain largely unmethylated in male and female germ cells and the early embryo. H3K4 methylation at CpG island promoters may protect these regions against de novo DNA methylation. Differences in DNA methylation deposition are known between male and female germ cells. During oocyte development, a subset of CpG islands are de novo methylated by DNMT3A. DNMT3A makes it into the fertilized zygote, which is odd considering the rapid demethylation of a paternal genome. It seems that specific regions of the paternal genome need to acquire DNA methylation in the early embryo, but what these regions are and how they impact transcription is unknown.
The laboratory of Matthew Lorincz (University of British Columbia, Canada) sought to determine which loci gain DNA methylation following fertilization. To do this, they undertook an allele-specific analysis of WGBS data from 2- cell (2C) F1 hybrid mouse embryos. These embryos are the result of breeding two different strains of mice, allowing strain-specific SNPs and INDELs to be used to discriminate the maternal from paternal copy of many genomic regions. In this model, they used H3K4me3 ChIP-seq and RNA-seq data to understand the impact of any DNA methylation changes they identified. Here’s what they found:
- In the paternal genome, robust DNA methylation gains occur at about 4% of the hypomethylated regions in sperm after fertilization
- These regions of paternal DNA methylation acquisition (PMA) are enriched for transcriptional start sites, particularly CG dense ones
- This de novo DNA methylation of paternal CpG islands is often accompanied by a reduction of H3K4me3
- Suggesting that this DNA methylation inhibits transcription from the paternal allele during early embryonic development
- PMA occurs in “motherless” but not “fatherless” blastocysts
- Demonstrating PMA is a bona-fide paternal genome effect
- In a maternal-specific DNMT3A knock out model, they found that PMA is lost and a subset of hypomethylated genes are upregulated from the paternal allele in the 4-cell embryo
- This indicates that PMA requires maternal DNMT3A
Lead author Julien Richard Albert shares, “We show in this study that in addition to the epigenetic mark that DNMT3A deposits in the oocyte, ‘inheritance’ of this DNA methyltransferase plays an unexpected role in de novo methylation of the incoming paternal genome in the zygote. What is really striking is that this allele-specific methylation transiently silences specific genes on the paternal genome, despite the global demethylation that is occurring at the same time.” So, let’s all make sure to acknowledge all the work Mom’s do for us, starting as soon as the sperm meets the egg.
Catch the full series in Nature Communications, October 2020