LAUSR

Background Paternal age has deleterious effects on the transmission of phenotypes to offspring, including higher prevalence of major psychiatric and neurodevelopmental disorders. Methods Here, we examined transgenerational transmission of selected somatic and cognitive phenotypes in mice and explored a possible epigenetic mechanism. Results F1 offspring of aged fathers had lower body weight and showed impairment in pup's vocalization, sensorimotor gating and spatial learning. From comprehensive methylome analyses, we identified in aged sperm 16 hypermethylated and 96 hypomethylated genomic loci. Motif analysis identified 19 potential REST/NRSF-binding sites in hypomethylated regions, which was confirmed as 37 motifs with actual binding of REST in the ChIP-seq database using ES-derived neural stem cells. Since we also found reduction of thickness in the neocortex, especially in the deep layer, we analyzed expression of potential REST-target genes. Discussion All of the data consistently support the scenario that hypomethylation in sperm due to paternal age may eventually result in ectopic binding of REST repressor to its target genes, downregulating their expression during brain development, thereby inducing behavioral abnormalities in the offspring.