Epigenetic profiling in Utx germline conditional knockouts and F1 offspring

Susceptibility to cancer is highly heritable, but much of this heritability remains unexplained. Some "missing" cancer heritability may be mediated by epigenetic changes in the parental germ line that do not involve transmission of genetic variants from parent to offspring. These data describe the finding that deletion of the chromatin regulator Utx (Kdm6a) in the mouse male germ line results in an elevated tumor incidence in genetically wild type offspring. This effect increases following passage through two successive generations of Utx male germline deletion, but is lost following passage through a wild type germ line. We find widespread redistribution of the H3K27me3 mark in Utx mutant germ cells, and further define approximately 200 regions marked by H3K27me3 that exhibit increased DNA methylation, both in sperm of Utx mutants and in somatic tissue of their progeny. These hypermethylated regions are located in functional enhancers and may alter regulation of genes involved in cancer initiation or progression. The results indicate that epigenetic changes in the male germ line can profoundly impact cancer susceptibility in adult offspring. Overall design: ChIP-seq, RRBS, and RNA-seq in cKO sperm and spermatids and in offspring bone marrow. ChIP-seq control spermatids.