Diet-Induced Hypomethylation in the Preneoplastic Liver Genetics and epigenetics of susceptibility to non-alcoholic steatohepatitis (NASH)

National Cancer Institute, Frederick MD

Investigators

Abstract

Diet-Induced Hypomethylation in the Preneoplastic Liver Genetics and epigenetics of susceptibility to non-alcoholic steatohepatitis (NASH) a comparative dietary study using Diversity Outbred (DO) mice Investigating the molecular basis of how epigenomic and genomic factors influence susceptibility to Nonalcoholic fatty liver disease (NAFLD) in humans using human NAFLD samples is desirable but frequently impractical. In contrast, using relevant animal models that resemble human NAFLD development may substantially overcome the many limitations of human-only studies and provide important clues regarding the molecular consequences of etiological factors linked to NAFLD susceptibility and severity. This Inter-Agency Agreement (IAA) will investigate the extent of molecular changes indicative of NAFLD-associated liver injury (including nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD) to assist in identifying susceptible individuals. Thus, we hypothesize that (a) the status of individual epigenomic hepatic phenotypes is a fundamental factor that predetermines susceptibility to NAFLD; and (b) an evaluation of epigenomic hepatic phenotypes in a genetically heterogeneous mouse population will assist in identifying individuals susceptible to NAFLD. To test the hypothesis, we plan to use a well-established dietary- (?Western Diet?) induced model of NASH in Diversity Outbred (DO) mice, a genetically heterogeneous mouse population. We will identify individual mice exhibiting the greatest susceptibility to NAFLD-associated liver injury in the genetically diverse population of mice and define the role of epigenetic alterations in the pathogenesis of NAFLD. Next generation sequencing, chromatin immunoprecipitation with DNA microarray methodology (Chip-on-chip) and quantitative RT-PCR will be used to assess whole genome-scale epigenomic changes and expression of protein-coding and non-coding RNAs, especially microRNAs, in plasma, white blood cells, and livers of treated and control mice.