# Molecular Basis of Sperm Methylome Response to Aging and Stress

## TL;DR

The paper explores how aging and stress affect sperm DNA methylation in regions linked to embryonic development, proposing that these changes may help diversify offspring traits to improve survival.

## Contribution

The study introduces a novel hypothesis that stochastic methylation variation in variable methylation regions (VMRs) explains sperm methylome responses to stress and aging.

## Key findings

- Changes in sperm DNA methylation due to aging and stress occur predominantly in VMRs associated with developmental genes.
- VMRs are enriched for a binding motif for ZFP42, an epigenetic remodeler involved in genomic imprinting.
- The nature of DNA regions, not the stressor type, determines the sperm methylome's response to aging and stress.

## Abstract

Many human and animal studies have shown that epigenetic programs in sperm are affected by aging and various stressful factors, and that these changes may have adverse effects on offspring health. Surprisingly, different stressors often affect similar sets of differentially methylated regions (DMRs) associated with developmental genes regardless of the nature of the stressor. We hypothesized that these unexplained patterns of sperm epigenome response may originate from stochastic epigenetic variation—a hypothesis suggesting that, in response to stressors, naturally variable methylation regions (VMRs) associated with morphogenic genes exhibit increased methylation variation to diversify offspring phenotypes and improve the chances of survival of the genetic lineage. We used data on sperm DNA methylation from mouse and rat experiments and demonstrated that, indeed, changes in DNA methylation in response to aging and various stressors predominantly occur in VMRs associated with major developmental pathways. Next, we propose a model that explains how a stochastic increase in methylation variation in VMRs results in either increased or decreased methylation in these regions. Further, we show that VMRs are enriched for a binding motif for ZFP42, an epigenetic remodeler involved in genomic imprinting. This knowledge may open opportunities to develop interventions to control epigenetic information transfer via germ cells.

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.