RNA sequencing of mice fed a high fat/high sucrose diet or a low fat/low sucrose diet

Publication Title: DNA methylation alters transcriptional rates of differentially expressed genes and contributes to pathophysiology in mice fed a high fat diet. It is now well established that an intrauterine environment altered by overnutrition or malnutrition can change gene expression patterns through epigenetic mechanisms that may persist through generations. However, it is less clear if overnutrition alters epigenetic control of gene expression in adults, or if whether such mechanisms contribute to the pathology of obesity. Here we test the hypothesis that exposure to a high fat diet alters hepatic DNA methylation and gene expression patterns, and explore the contribution of such changes to the pathophysiology of overnutrition. RNA-seq and targeted high-throughput bisulfite DNA sequencing were used to undertake a systematic analysis of the hepatic response to a high fat diet. A subset of genes was found whose expression levels were altered in concert with DNA methylation changes. Using chromatin immunoprecipitation of RNA polymerase, we determined that hypermethylation correlated with decreased transcription of two of the genes, Phlda1 and Onecut1. A subnetwork of these genes and their nearest neighbors was generated from an existing Bayesian gene network that contained numerous hepatic regulatory genes involved in lipid and body weight homeostasis. Hepatic-specific depletion of Phlda1 in mice decreased the genes in the subnetwork, and led to increased oil droplet size in standard chow-fed mice, an early indicator of steatosis, validating the contribution of this gene to the phenotype. Overall design: 14 mice fed either a high fat/high sucrose (n=7) or low fat/low sucrose (n=7) diet.

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Zhang P, Chu T, Dedousis N, Mantell BS, Sipula I, Li L, Bunce KD, Shaw PA, Katz LS, Zhu J, Argmann C, O'Doherty RM, Peters DG, Scott DK