Department of Medicine, Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
Elizabeth A Morgan
Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
Zhicong Liao
Department of Genetics, Yale School of Medicine, New Haven, United States; Yale Cancer Center, Yale School of Medicine, New Haven, United States
Roderick T Bronson
Department of Pathology, Tufts University School of Medicine and Veterinary Medicine, North Grafton, United States
Benjamin L Ebert
Department of Medicine, Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
Whitehead Institute, Cambridge, United States; Department of Biology, Massachusetts Institute of Technology, Cambridge, United States; Howard Hughes Medical Institute, Whitehead Institute, Cambridge, United States
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.
