Sperm Histone H3 Lysine 4 tri-methylation serves as a metabolic sensor of paternal obesity and is associated with the inheritance of metabolic dysfunction

Abstract

AbstractParental environmental exposures can strongly influence descendant risks for adult disease. Metabolic disorders arise from the intersection of environmental and genetic risk factors, with epigenetic inheritance being at the center of the familial cycle of transgenerational disease. How paternal high-fat diet changes the sperm chromatin leading to the acquisition of metabolic disease in offspring remains controversial and ill-defined. Using a genetic model of epigenetic inheritance, we investigated the role of histone H3 lysine 4 methylation (H3K4me3) in the paternal transmission of metabolic dysfunction. We show that obesity-induced alterations in sperm H3K4me3 associated with offspring phenotypes and corresponded to embryonic and placental chromatin profiles and gene expression. Transgenerational susceptibility to metabolic disease was only observed when grandsires had a pre-existing modified sperm epigenome due to overexpression of the histone demethylase KDM1 in the male germline. This non-DNA based knowledge of inheritance has the potential to improve our understanding of how environment shapes heritability and may lead to novel routes for the prevention of disease.