Molecular Basis of Sperm Methylome Response to Aging and Stress

Aging and stress-related factors affect sperm DNA methylation in regions associated with genes responsible for embryonic development. The stochastic epigenetic variation hypothesis holds potential to explain these patterns, proposing that, in response to stressors, naturally variable methylation regions (VMRs) associated with morphogenetic genes exhibit increased methylation variation to diversify phenotypes and improve the chances of survival of the genetic lineage. Here, we test predictions from this hypothesis using mouse and rat sperm DNA methylation data from publicly available sources. Specifically, we identify VMRs and analyze their overlap with regions differentially methylated (DMRs) in response to aging, stressors, and with various genomic elements. We demonstrate that the nature of the DNA regions, rather than the nature of the stressor, determines the response of the sperm methylome to aging and stress, and propose a model that explains shifts in methylation within VMRs through stochastic changes, whereby initially hypermethylated regions lose methylation and initially hypomethylated regions gain methylation. VMRs are depleted of open chromatin regions and histones in male germ cells and are enriched for a binding motif for ZFP42, an epigenetic remodeler. This knowledge may open opportunities for the development of interventions to control epigenetic information transfer via germ cells.