Khdc3 Regulates Metabolism Across Generations in a DNA-Independent Manner [liver]

Genetic variants can alter the profile of heritable molecules such as small RNAs in sperm and oocytes, and in this manner ancestral genetic variants can have a significant effect on offspring phenotypes even if they are not themselves inherited. Here we show that wild type female mice descended from ancestors with a mutation in the mammalian germ cell gene Khdc3 have hepatic metabolic defects that persist over multiple generations. We find that genetically wild type females descended from Khdc3 mutants have transcriptional dysregulation of critical hepatic metabolic genes, which persist over multiple generations and pass through both female and male lineages. This was associated with dysregulation of hepatically-metabolized molecules in the blood of these wild type mice with mutational ancestry. The oocytes of Khdc3­-null females, as well as their wild type descendants, had dysregulation of multiple small RNAs, suggesting that these epigenetic changes in the gametes transmit the phenotype between generations. Our results demonstrate that ancestral mutation in Khdc3 can produce transgenerational inherited phenotypes, potentially indefinitely. Overall design: Comparison of hepatic transcriptomes in wild type (WT) and Khdc3-null (KO) mice of different genetic ancestries, at 8 weeks of age. WT mice are descended from WT ancestors, while KO mice are descended from KO ancestors. WT_star females are genetically WT mice descended from heterozygous parents and a combination of WT and KO grandparents, while KO_star females are genetically KO mice that are similarly descended from heterozygous parents and a combination of WT and KO grandparents