Multi-Omic Data Analysis Supporting the Plausibility of Human Aging Sperm-Mediated Epigenetic Inheritance

Sperm DNA methylation changes have been implicated in the increased adverse pregnancy and offspring disease risks associated with advanced paternal age. Here, an analysis of diverse, publicly available human multi-omic data is presented that assesses the mechanistic plausibility for these changes to exert cross-generational developmental and health effects. First, differentially methylated CpGs in aging sperm DNA were found to specifically overrepresent differentially methylated CpGs in aging and disease soma. Next, sperm and soma common CpGs, compared to sperm and soma unique CpGs, showed higher enrichment for regulatory regions of developmental genes. Further, genes associated with the common CpGs, compared to the unique CpGs, showed higher enrichment for genes differentially expressed during both preimplantation and postimplantation development, and most crucially for epigenetic inheritance amenability, in early embryos known to undergo paternal methylation-associated gene regulation and in epigenetically reprogrammed primordial germ cells. Higher enrichment is likewise also observed for aging- and disease-associated genes. These results suggest that aging sperm methylation marks may possibly affect early embryonic gene expression, with downstream somatic and germline gene regulatory consequences leading to reestablishment of methylation marks, developmental anomalies, and inheritance of disease phenotypes. This data-grounded mechanistic possibility could be relevant in epigenetic inheritance in general.