TY - JOUR TI - Intergenerational epigenetic inheritance of cancer susceptibility in mammals AU - Lesch, Bluma J AU - Tothova, Zuzana AU - Morgan, Elizabeth A AU - Liao, Zhicong AU - Bronson, Roderick T AU - Ebert, Benjamin L AU - Page, David C A2 - van Lohuizen, Maarten A2 - Struhl, Kevin A2 - Kelsey, Gavin VL - 8 PY - 2019 DA - 2019/04/09 SP - e39380 C1 - eLife 2019;8:e39380 DO - 10.7554/eLife.39380 UR - https://doi.org/10.7554/eLife.39380 AB - Susceptibility to cancer is heritable, but much of this heritability remains unexplained. Some ‘missing’ heritability may be mediated by epigenetic changes in the parental germ line that do not involve transmission of genetic variants from parent to offspring. We report that deletion of the chromatin regulator Kdm6a (Utx) in the paternal germ line results in elevated tumor incidence in genetically wild type mice. This effect increases following passage through two successive generations of Kdm6a male germline deletion, but is lost following passage through a wild type germ line. The H3K27me3 mark is redistributed in sperm of Kdm6a mutants, and we define approximately 200 H3K27me3-marked regions that exhibit increased DNA methylation, both in sperm of Kdm6a mutants and in somatic tissue of progeny. Hypermethylated regions in enhancers may alter regulation of genes involved in cancer initiation or progression. Epigenetic changes in male gametes may therefore impact cancer susceptibility in adult offspring. KW - epigenetics KW - transgenerational inheritance KW - histone modification KW - gametes KW - spermatogenesis KW - cancer JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -