Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development

Abstract

Although more studies are demonstrating that a father’s environment can influence child health and disease, the molecular mechanisms underlying non-genetic inheritance remain unclear. It was previously thought that sperm exclusively contributed its genome to the egg. More recently, association studies have shown that various environmental exposures including poor diet, toxicants, and stress, perturbed epigenetic marks in sperm at important reproductive and developmental loci that were associated with offspring phenotypes. The molecular and cellular routes that underlie how epigenetic marks are transmitted at fertilization, to resist epigenetic reprogramming in the embryo, and drive phenotypic changes are only now beginning to be unraveled. Here, we provide an overview of the state of the field of intergenerational paternal epigenetic inheritance in mammals and present new insights into the relationship between embryo development and the three pillars of epigenetic inheritance: chromatin, DNA methylation, and non-coding RNAs. We evaluate compelling evidence of sperm-mediated transmission and retention of paternal epigenetic marks in the embryo. Using landmark examples, we discuss how sperm-inherited regions may escape reprogramming to impact development via mechanisms that implicate transcription factors, chromatin organization, and transposable elements. Finally, we link paternally transmitted epigenetic marks to functional changes in the pre- and post-implantation embryo. Understanding how sperm-inherited epigenetic factors influence embryo development will permit a greater understanding related to the developmental origins of health and disease.

Trim66’s paternal deficiency causes intrauterine overgrowth

“…Paternal effect phenotypes in mammals are rare and can have several possible causes (Rando, 2012; Lismer & Kimmins, 2023). For example, the loss-of-function of an imprinted gene normally expressed from the paternally inherited allele (Li et al, 1999).…”

Epigenetic aging of mammalian gametes

“…As with the chromatin landscape, sperm DNA methylation patterns are quite unique. Unlike the intermediate methylation levels found in oocytes (Smallwood et al, 2011), the level of sperm genome methylation is ~70% on average (Lismer & Kimmins, 2023;Molaro et al, 2011;Shea et al, 2015). This methylation is highly critical for the progression of the spermatogenesis process (Barau et al, 2016;Bourc'his & Bestor, 2004;Dura et al, 2022) Yet, specific areas present with hypomethylation, mostly CpG islands of developmental regulatory genes as the HOX genes (Hammoud et al, 2009).…”

Teratogenesis and the epigenetic programming of congenital defects: Why paternal exposures matter

“…During spermatogenesis, most histones are replaced by protamines. However, select genomic loci in sperm retain histones, potentially transferring a range of posttranslational modifications and epigenetic information to the zygotic genome (Lismer & Kimmins, 2023). Significantly, emerging research reveals that sperm derived from males exposed to alcohol, a folic acid deficient diet, a high-fat diet, and the herbicide glufosinate-ammonium all display altered amounts of dimethylated histone H3 lysine 9 (H3K9me2) or trimethylated histone H3 lysine 4 (H3K4me3) (Y. S. Bedi et al, 2022;Cambiasso et al, 2022;Claycombe-Larson et al, 2020;Yoshida et al, 2020;Lismer et al, 2021;Ma et al, 2021;Pepin et al, 2022;Terashima et al, 2015).…”

“…Significantly, emerging research reveals that sperm derived from males exposed to alcohol, a folic acid deficient diet, a high-fat diet, and the herbicide glufosinate-ammonium all display altered amounts of dimethylated histone H3 lysine 9 (H3K9me2) or trimethylated histone H3 lysine 4 (H3K4me3) (Y. S. Bedi et al, 2022;Cambiasso et al, 2022;Claycombe-Larson et al, 2020;Yoshida et al, 2020;Lismer et al, 2021;Ma et al, 2021;Pepin et al, 2022;Terashima et al, 2015). Notably, stressor-induced changes in H3K4me3 predominantly map to transcriptionally active loci in the early embryo and placenta but display very little to no conservation with chromatin changes or altered gene expression identified in the somatic cells of adult offspring, arguing against the direct inheritance of these changes as the epigenetic memory of disease (Lismer & Kimmins, 2023). Therefore, how changes in sperm chromatin structure influence early embryonic transcription and, in turn, modify development and disease onset remain open questions requiring further investigation.…”