Identification of differentially methylated region (DMR) networks associated with progression of nonalcoholic fatty liver disease

Sci Rep. 2018 Sep 11;8(1):13567. doi: 10.1038/s41598-018-31886-5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / metabolism*
  • Blood Glucose / metabolism
  • Body Mass Index
  • Case-Control Studies
  • CpG Islands
  • DNA Methylation
  • Disease Progression
  • Epigenesis, Genetic*
  • Female
  • Gene Regulatory Networks*
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • Hyperglycemia / genetics
  • Hyperglycemia / metabolism*
  • Hyperglycemia / pathology
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology

Substances

  • Blood Glucose