Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring

A father’s lifestyle impacts offspring health; yet, the underlying molecular mechanisms remain elusive. We hypothesized that a diet that changes methyl donor availability will alter the sperm and embryo epigenomes to impact embryonic gene expression and development. Here, we demonstrate that a folate-deficient (FD) diet alters histone H3 lysine 4 trimethylation (H3K4me3) in sperm at developmental genes and putative enhancers. A subset of H3K4me3 alterations in sperm are retained in the pre-implantation embryo and associated with deregulated embryonic gene expression. Using a genetic mouse model in which sires have pre-existing altered H3K4me2/3 in sperm, we show that a FD diet exacerbates alterations in sperm H3K4me3 and embryonic gene expression, leading to an increase in developmental defect severity. These findings imply that paternal H3K4me3 is transmitted to the embryo and influences gene expression and development. It further suggests that epigenetic errors can accumulate in sperm to worsen offspring developmental outcomes. [Display omitted] •Postnatal paternal folate deficiency alters sperm H3K4me3 at developmental loci•Sperm H3K4me3 aberrations are retained in the embryo & associated with birth defects•Deregulated embryo gene expression is concordant with sperm H3K4me3 alterations•Folate deficiency in KDM1A transgenics enhances sperm H3K4me3 levels and birth defects Lismer et al. reveal that sperm chromatin is sensitive to dietary stress. By tracking sperm H3K4me3 in the pre-implantation embryo, they show that H3K4me3 alterations are retained and linked to deregulated gene expression. Multiple epigenetic stressors enhance sperm H3K4me3 changes and lead to increased birth defect severity in the offspring.