Investigating the epigenetic mechanism behind transgenerational inheritance in germ cells of mice (360G-Wellcome-105356_Z_14_A)

Poor nutrition leads to an increased risk for disease, which may be passed on to subsequent generations with a normal diet. This non-genetic mode of inheritance is not well understood. The goal of my project is to investigate this epigenetic mechanism by focusing on the inheritance of altered DNA methylation in sperm from a genetic mouse model of abnormal folate metabolism (Mtrrgt model). Folate is part of the one-carbon metabolism necessary for DNA methylation. Previously, the Watson lab reported that when either maternal grandparent carried the Mtrrgt mutation, their wildtype grandprogeny displayed developmental phenotypes and dysregulated DNA methylation. How this epigenetic instability is inherited to disrupt development is unclear. My hypothesis is that abnormal DNA methylation patterns caused by Mtrr deficiency escape epigenetic reprogramming, are passed onto subsequent wildtype generations and disrupt developmentally-important gene expression. My specific goals are: 1. To prove that Mtrrgt mutants have not acquired additional genetic mutations. 2.To determine whether alterations in DNA methylation patterns in sperm from the Mtrrgt model are present and inherited. 3.To morphologically and molecularly analyze testes structure and spermatogenesis in Mtrr mutants. Understanding mechanisms of epigenetic inheritance will help us predict how our environment affects our descendants’ disease risk.