DNA methylation alters transcriptional rates of differentially expressed genes and contributes to pathophysiology in mice fed a high fat diet

Abstract

ObjectiveOvernutrition can alter gene expression patterns through epigenetic mechanisms that may persist through generations. However, it is less clear if overnutrition, for example a high fat diet, modifies epigenetic control of gene expression in adults, or by what molecular mechanisms, or if such mechanisms contribute to the pathology of the metabolic syndrome. Here we test the hypothesis that a high fat diet alters hepatic DNA methylation, transcription and gene expression patterns, and explore the contribution of such changes to the pathophysiology of obesity.MethodsRNA-seq and targeted high-throughput bisulfite DNA sequencing were used to undertake a systematic analysis of the hepatic response to a high fat diet. RT-PCR, chromatin immunoprecipitation and in vivo knockdown of an identified driver gene, Phlda1, were used to validate the results.ResultsA high fat diet resulted in the hypermethylation and decreased transcription and expression of Phlda1 and several other genes. A subnetwork of genes associated with Phlda1 was identified 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 expression of 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.ConclusionsWe conclude that a high fat diet alters the epigenetics and transcriptional activity of key hepatic genes controlling lipid homeostasis, contributing to the pathophysiology of obesity.

Effect of Age, High-Fat Diet, and Rat Strain on Serum Biomarkers and Telomere Length and Global DNA Methylation in Peripheral Blood Mononuclear Cells

“…It has been observed that prolonged high-fat diet maintenance during adulthood in mice dynamically changed DNA methylation and expression of genes in fat-specific depots, such as gonadal adipose tissue 23 . In addition, a high-fat diet resulted in hyper-methylation and decreased transcription and expression of important hepatic genes controlling lipid homeostasis in a mouse model 24 . The influence of diet on global DNA methylation of PBMCs in the current study was more varied compared to telomere length, but also dependent on animal strain.…”

Myc Is Required for Adaptive β-Cell Replication in Young Mice but Is Not Sufficient in One-Year-Old Mice Fed With a High-Fat Diet

“…Increased DNA Methylation in E-Boxes in Promoter/ Enhancer Areas of Cell Cycle Genes in 1-Year-Old Mice Fed Short-term HFD An HFD has been reported to induce methylation changes in gene regulatory regions in multiple tissues, including pancreatic b-cells (45,46). Therefore, we used a targeted DNA methylation analysis (47) to investigate the DNA methylation pattern of the 21 Myc-targeting cell cycle genes identified in Fig.…”

Nutritional Factors Modulating Alu Methylation in an Italian Sample from The Mark-Age Study Including Offspring of Healthy Nonagenarians

“…In fact, it has been demonstrated that a VLDL-and LDL-rich lipoprotein mix induces de novo DNA methylation in THP-1 macrophages via the activation of DNMT1 [58]. Other evidence reports that a high-fat diet promotes hypermethylation and decreases the transcription of hepatic genes controlling lipid homeostasis in a mouse model [59]. It also affects global DNA methylation in rat PBMCs and mouse heart [60,61].…”