High-fat diet caused widespread epigenomic differences on hepatic methylome in rat

Abstract

Pan YX. High-fat diet caused widespread epigenomic differences on hepatic methylome in rat. Physiol Genomics 47: 514 -523, 2015. First published July 21, 2015; doi:10.1152/physiolgenomics.00110.2014.-A high-fat (HF) diet is associated with progression of liver diseases. To illustrate genome-wide landscape of DNA methylation in liver of rats fed either a control or HF diet, two enrichment-based methods, namely methyl-DNA immunoprecipitation assay with high-throughput sequencing (MeDIP-seq) and methylation-sensitive restriction enzyme sequencing (MRE-seq), were performed in our study. Rats fed with the HF diet exhibited an increased body weight and liver fat accumulation compared with that of the control group when they were 12 wk of age. Genome-wide analysis of differentially methylated regions (DMRs) showed that 12,494 DMRs induced by HF diet were hypomethylated and 6,404 were hypermethylated. DMRs with gene annotations [differentially methylated genes (DMGs)] were further analyzed to show gene-specific methylation profile. There were 88, 2,680, and 95 hypomethylated DMGs identified with changes in DNA methylation in the promoter, intragenic and downstream regions, respectively, compared with fewer hypermethylated DMGs (45, 1,623, and 50 in the respective regions). Some of these genes also contained an ACGT cis-acting motif whose DNA methylation status may affect gene expression. Pathway analysis showed that these DMGs were involved in critical hepatic signaling networks related to hepatic development. Therefore, HF diet had global impacts on DNA methylation profile in the liver of rats, leading to differential expression of genes in hepatic pathways that may involve in functional changes in liver development. DMR; DNA hypomethylation; gene expression; high-fat diet; MeDIP THE INTERACTION BETWEEN NUTRITIONAL and epigenetic influences on the gene regulation is of great interest to researchers (27). For decades, due to the limitation and cost of the experimental technology for detecting DNA methylation (6), most studies focused on how diet affects the promoter methylation profile of a single gene and its relationship with gene expression. Recent advancements in sequencing-based DNA methylation profiling methods including methyl-DNA immunoprecipitation assay in combination with high-throughput sequencing (MeDIP-seq) and methylation-sensitive restriction enzyme sequencing (MRE-seq) have allowed researchers to map out DNA methylation profile in a genome-wide fashion (30).Consumption of a high-fat (HF) diet may cause numerous health consequences, including extensive hepatic triglyceride accumulation, insulin resistance, oxidative damage, and chronic low-grade inflammation, which leads to progression of liver diseases and fibrosis (2,8,34). Metabolism and cell cycle-related genes in liver tissue are known to be subject to regulation by DNA methylation. For instance, methylation intensity at specific CpG sites on Esr1 (7) and stearoyl-CoA desaturase 1 (Scd1) (29), glucokinase, pyruvate kinase (18), and MTTP (4) genes ...

Genome-wide hepatic DNA methylation changes in high-fat diet-induced obese mice

“…It is concurrent with previous findings that HFD causes changes in methylation status of specific genes involved in glucose and lipid metabolism of liver, inflammation, and liver development [1011121327]. In a previous study that investigated the genome-wide effect of HFD on liver DNA methylation starting from mouse conception, annotated genes with DMRs were enriched in signaling pathways of liver steatosis and liver development such as cell morphogenesis, developmental growth, response to stimuli, signal transduction, and triacylglycerol biosynthesis [14]. Therefore, results from this study could complement current knowledge by providing genome-wide evidence that HFD affects biological networks associated with liver lipid accumulation and liver diseases even during the adulthood.…”

“…There was a similar high-throughput approach previously, in which the effect of HFD was examined from mouse conception through the adulthood [14]. The current study differs in its design from the previous study in that it examined the effect of HFD consumption during the adulthood only.…”

“…However, regarding HFD-induced changes in hepatic DNA methylation, genome-wide analysis using high-throughput methods is limited and majority of previous studies have investigated DNA methylation in gene-specific way. In a study that examined the impact of HFD on genome-wide hepatic DNA methylation, animals were exposed to HFD from conception onward into adulthood [14]. DNA methylation patterns are established during prenatal and early postnatal period and generally persist through adulthood.…”

Maternal folate depletion during early development and high fat feeding from weaning elicit similar changes in gene expression, but not in DNA methylation, in adult offspring

“…We have previously reported that folate depletion during pregnancy evoked approximately three times more changes in expression than in DNA methylation (expression of 989 genes v. methylation of 333 gene promoters) in the fetal liver . Others have reported genome‐wide, but also relatively small, changes in DNA methylation in the liver of rat offspring from dams fed a high‐fat diet (45% of energy from fat) throughout gestation and lactation and to the offspring from weaning until 12 weeks of age .…”

“…Others have reported genome-wide, but also relatively small, changes in DNA methylation in the liver of rat offspring from dams fed a high-fat diet (45% of energy from fat) throughout gestation and lactation and to the offspring from weaning until 12 weeks of age [68]. Whilst we observed simultaneous changes in gene expression and promoter DNA methylation in response to both nutritional exposures investigated, we found no significant overlap between gene lists for which expression and promoter methylation were altered in response to a given exposure.…”