Aging-associated alterations of sperm-retained histones influence transcriptional regulation in mice offspring

Advanced paternal aging is associated with autism spectrum disorder (ASD) in progeny. While the causative agents have not yet been fully determined, several factors, including genetic and epigenetic mutations, have been suggested. In this study, we examined whether paternal aging alters sperm-retained histones and found aging-associated alterations in H3K27me3 and H3K79me3. In young sperm, most H3K27me3 and H3K79me3 exist as bivalent modifications concominant with H3K4me3, respectively, and are enriched at transcription starting sites (TSSs) of neuro-developmental genes and spermatogenesis-related genes, respectively. In old sperm, both lose their relative accumulation at the TSSs, while their total quantity rather increase. H3K27me3-marked genes in young sperm show a significant correlation with altered gene expression in the hippocampus of old-father offspring accompanied by enriched GO terms related to ASD.