Alcohol induced increases in sperm Histone H3 lysine 4 trimethylation correlate with increased placental CTCF occupancy and altered developmental programming

Abstract

Using a mouse model, studies by our group reveal that paternal preconception alcohol intake affects offspring fetal-placental growth, with long-lasting consequences on adult metabolism. Here, we tested the hypothesis that chronic preconception male alcohol exposure impacts histone enrichment in sperm and that these changes are associated with altered developmental programming in the placenta. Using chromatin immunoprecipitation, we find alcohol-induced increases in sperm histone H3 lysine 4 trimethylation (H3K4me3) that map to promoters and presumptive enhancer regions enriched in genes driving neurogenesis and craniofacial development. Given the colocalization of H3K4me3 with the chromatin binding factor CTCF across both sperm and embryos, we next examined CTCF localization in the placenta. We find global changes in CTCF binding within placentae derived from the male offspring of alcohol-exposed sires. Furthermore, altered CTCF localization correlates with dysregulated gene expression across multiple gene clusters; however, these transcriptional changes only occur in male offspring. Finally, we identified a correlation between genomic regions exhibiting alcohol-induced increases in sperm H3K4me3 and increased CTCF binding in male placentae. Collectively, our analysis demonstrates that the chromatin landscape of sperm is sensitive to chronic alcohol exposure and that a subset of these affected regions exhibits increased placental CTCF enrichment.

Paternal alcohol exposures program intergenerational hormetic effects on offspring fetoplacental growth

“…We have observed suppression of pathways regulating oxidative phosphorylation in a high-dose model of early gestational EtOH exposure and recently identified this same signature in male placentae sired by EtOH-exposed fathers ( Chang et al, 2021 ; Thomas et al, 2021 ). Further, we have identified alcohol-induced increases in H3K4me3 in alcohol-exposed sperm ( Bedi et al, 2022 ). Therefore, we speculate that low levels of oxidative stress program epigenetic changes in sperm, which suppress oxidative stress response pathways in the offspring, including the mTOR, EIf2, and Sirtuin signaling pathways.…”

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

“…Still further evidence that sperm H3K4me3 serves as an environmental sensor that influences embryo development, was shown in a paternal alcohol exposure mouse model. Alcohol exposure increased H3K4me3 at neurogenesis and craniofacial promoters in sperm and led to correlated increases in CTCF in next generation placentae at the same genomic loci 113 .…”

Nucleosomes in mammalian sperm: conveying paternal epigenetic inheritance or subject to reprogramming between generations?

“…Alterations in sperm histone content, composition and distribution have been reported upon exposures of males to chemicals such as vinclozolin, DTT or ethanol as well as to dietary factors including low-protein or folate-deficient diets 107 , 115 , 116 . For example, males fed with low protein diet contain proportionally lower levels of H3K9me2 in sperm [117] .…”