Paternal regulation of H3K4 methylation supports tumor suppressor networks in mammals intergenerationally
Year: 2026
Type: preprint
Abstract: Paternally-inherited epigenetic information can influence phenotype in offspring (1). Here, we identify a critical mechanistic contribution of KDM6A (UTX), an X-linked histone modifier and tumor suppressor, in regulating transmissible epigenetic information in mammalian sperm. Paternal loss of KDM6A increases cancer risk in genetically wild type offspring, but how Kdm6a knockout sperm transmit this effect at the molecular level is unknown (2). We find that KDM6A functions in spermatogenesis to promote methylation of histone H3 lysine 4 (H3K4) via selective interaction with the COMPASS complex methyltransferase KMT2C (MLL3). KMT2C and KDM6A are coordinately recruited to promoters of active genes in spermatogenic cells, contrasting with recruitment to intergenic enhancers in other cell types (3, 4). Loss of KDM6A disrupts H3K4 methylation at promoters of tumor suppressor genes in spermatogonia, and some of these defects persist in epididymal sperm and correspond to impaired expression in preimplantation embryos. These genes are also misregulated in normal and malignant hematopoietic tissue of genetically wild type offspring, indicating that impaired H3K4 methylation in KDM6A-deficient male germ cells may preferentially alter regulation of tumor suppressor gene networks in development across generations.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: American Cancer Society, Yale University, Yale Cancer Center, Hope Funds for Cancer Research, Searle Scholars Program, National Institutes of Health, National Cancer Institute, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Defining the role of DOT1L in chromocenter stabilization pre- and post-fertilization, G3257551317, Genome-epigenome interactions in heritable lung cancer risk, G5793416736, G6417110059, G7229188214, Germline Utx mutation as a model for transgenerational epigenetic inheritance, Defining signatures of epigenetic sensitization to lung cancer in a mouse model
OpenAlex ID: W7204912684