467: Epigenomic response of the fetal liver to maternal high-fat diet and resveratrol supplementation

The effects of an adverse gestational environment can persist postnatally, including an increased risk of adult metabolic diseases. In a non-human primate model of maternal high-fat diet (MHFD) we previously demonstrated signs of non-alcoholic fatty liver disease in the fetal livers of MHFD offspring. We further discovered an associated increase in histone H3K14 acetylation and decrease in histone deacetylase SIRT1 activity. To better understand the mechanism of the developmental origins of obesity, we aimed to establish the conserved alterations in the fetal hepatic epigenome in response to MHFD and determine the effect of SIRT1 activation on chromatin structure. Prior to and throughout pregnancy, Japanese macaques were placed on a control diet (CD) or MHFD with or without suplementation with resveratrol (480 mg/d). An additional cohort of dams previously exposed to HFD were fed CD to investigate the effects of diet reversal. At gestational day 130 (early 3rd trimester), pregnancies were terminated and tissues collected for analysis. Chromatin immunoprecipitation of activating and repressive epigenetic histone marks were performed on fetal livers from each group followed by high-throughput sequencing (ChIP-seq). Data were analyzed for differential histone binding, functional enrichment, and associated gene pathways. Samples were sequenced on the Illumina platform generating over 1.7 billion reads. After mapping to the reference macaque genome peaks were called and differential binding determined. As expected, histone H3K14ac was found to be enriched surrounding the transcription start site (TSS, Fig1a) with increased binding in fetal livers exposed to MHFD. Resveratrol treatment was associated with a reversal of H3K14ac near the TSS, decreased binding to the promoter region, and a relative increase in intergenic H3K14ac (Fig2a,b). In-depth characterization of the fetal epigenomic response to maternal dietary perturbations has yielded a greater understanding of the mechanisms behind the developmental origins of metabolic dysfunctions. We demonstrated that activation of SIRT1 reversed the effect of MHFD on the fetal epigenome. These studies may aid in the development of preventative or therapeutic interventions to mitigate the outcome of an unhealthy maternal lifestyle on fetal development and risk of disease.View Large Image Figure ViewerDownload Hi-res image Download (PPT)