600: Maternal high-fat diet and the fetal liver: Integrative analysis of epigenomic and transcriptomic reprogramming in primates

An unfavorable intrauterine environment due to poor maternal nutrition has been implicated in the developmental origins of increased metabolic disease risk in offspring. We previously demonstrated the development of fatty liver disease in Japanese macaque fetuses exposed to maternal high fat diet (HFD), accompanied by changes in epigenetic regulator activity. To characterize the molecular aspects of fetal reprogramming with changes in maternal diet and obesity status, we investigated the associated alterations in the hepatic epigenome and transcriptome using this non-human primate model. Socially housed Japanese macaque dams were fed HFD (35% fat) or isocaloric control diet (CTR, 16% fat) prior to pregnancy. To distinguish the effects of maternal HFD from maternal obesity, a subset of the HFD cohort was fed control chow during pregnancy (HFD-Rev). In the third trimester at gestational day 130, offspring were delivered by Cesarean for tissue collection and analysis. Sequencing was performed on fetal hepatic RNA (N=46) and immunoprecipitated chromatin (N=16). Histone marks associated with gene activation (H3K4me3, H3K9ac and H3K14ac) and repression (H3K9me3 and H3K27me3) were analyzed for epigenetic regulation and integrated with differential gene expression. Examination of the transcriptome by principal component analysis demonstrated separation of expression profiles by virtue of maternal diet (Fig 1A). Differentially expressed genes were detected between all diet groups (Fig 1b, q < 0.05) with perturbations in several core metabolic pathways. Further investigation revealed significantly alterated expression of key metabolic genes between HFD and CTR, including GLUT2 (Fig 2C, q = 1e-4), FASN (q = 1e-4), GCKR (q = 9e-3), and LDLR (q = 0.01). Of these, only LDLR (q < 0.1) was significantly different in the HFD-Rev group. H3K14ac epigenomic distribution differed by diet, and H3K4me3 occupancy at metabolic genes transcription start sites was increased with HFD but not reversal (Fig 2B). Characterization of the molecular mechanisms behind the effects of MHFD and obesity on the fetus is crucial to understanding their influence on disease risk in the offspring. We have detailed the changes associated with MHFD in epigenetic regulation, gene expression, and metabolic pathways in the fetal liver.View Large Image Figure ViewerDownload Hi-res image Download (PPT)