Abstract
The progression of nonalcoholic fatty liver disease (NAFLD) is affected by epigenetics. We performed differentially methylated region (DMR) and co-methylation analyses to identify DMR networks associated with the progression of NAFLD. DMRs displaying differences in multiple consecutive differentially methylated CpGs between mild and advanced NAFLD were extracted. The average values of topological overlap measures for the CpG matrix combining two different DMRs were calculated and two DMR networks that strongly correlated with the stages of fibrosis were identified. The annotated genes of one network included genes involved in transcriptional regulation, cytoskeleton organization, and cellular proliferation. The annotated genes of the second network were primarily associated with metabolic pathways. The CpG methylation levels in these networks were strongly affected by age and fasting plasma glucose levels, which may be important co-regulatory factors. The methylation status of five DMRs in the second network was reversible following weight loss. Our results suggest that CpG methylation in DMR networks is regulated concomitantly via aging and hyperglycemia and plays important roles in hepatic metabolic dysfunction, fibrosis, and potential tumorigenesis, which occur during the progression of NAFLD. By controlling weight and blood glucose levels, the methylation of DMRs in the second network may be reduced.
Highlights
Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver diseases ranging from non-alcoholic fatty liver, which is a benign and non-progressive condition, to nonalcoholic steatohepatitis, which can progress to liver cirrhosis and hepatocellular carcinoma[1,2]
We identified two core gene networks involved in nonalcoholic fatty liver disease (NAFLD) progression: one contained a scale-free network with four hub genes associated with increases in fibrosis and tumorigenesis, and the other consisted of a random network associated with mitochondrial dysfunction[11]
We used weighted gene co-expression network analysis (WGCNA) and performed a co-methylation analysis of 3,683 CpGs in 610 differentially methylated region (DMR) to investigate the DMR networks associated with NAFLD progression in a Japanese cohort
Summary
Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver diseases ranging from non-alcoholic fatty liver, which is a benign and non-progressive condition, to nonalcoholic steatohepatitis, which can progress to liver cirrhosis and hepatocellular carcinoma[1,2]. The hypermethylation of CpG99 in the regulatory region of PNPLA3 and the subsequent suppression of PNPLA3 mRNA levels were observed in the livers of patients with NAFLD in advanced stages of fibrosis. To evaluate the epigenetic status of the NAFLD liver, we performed whole hepatic mRNA-sequencing followed by weighted gene co-expression network analysis (WGCNA). Our co-methylation analysis demonstrated that one of the modules was associated with an increase in the immune response, while another was associated with mitochondrial dysfunction, impaired lipid metabolism, and reduced oxidoreductase activity in advanced NAFLD. In the present study, we applied network modeling to the DMRs identified in mild and advanced NAFLD livers in a Japanese population to investigate the systematic regulatory DMR networks associated with disease progression
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