Identification of the genomic region under epigenetic regulation during non‐alcoholic fatty liver disease progression

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Abstract
Aim: The progression of non‐alcoholic fatty liver disease (NAFLD) is affected by epigenetics. We undertook co‐methylation and differentially methylated region (DMR) analyses to identify the genomic region that is under epigenetic regulation during NAFLD progression.Methods: We collected liver biopsy specimens from 60 Japanese patients with NAFLD and classified these into mild (fibrosis stages 0–2) or advanced (fibrosis stages 3–4) NAFLD. We carried out a genome‐wide DNA methylation analysis and identified the differentially methylated CpGs between mild and advanced NAFLD. Differentially methylated regions with multiple consecutive differentially methylated CpGs between mild and advanced NAFLD were extracted.Results: Co‐methylation analysis showed that individual differentially methylated CpG sites were clustered into three modules. The CpG sites clustered in one module were hypomethylated in advanced NAFLD and their annotated genes were enriched for “immune system” function. The CpG sites in another module were hypermethylated and their annotated genes were enriched for “mitochondria” or “lipid particle”, and “lipid metabolism” or “oxidoreductase activity”. Hypomethylated DMRs included tumorigenesis‐related genes (FGFR2,PTGFRN, andZBTB38), the expressions of which are upregulated in advanced NAFLD. Tumor suppressorMGMThad two DMRs and was downregulated. Conversely,FBLIM1andCYR61, encoding proteins that reduce cell proliferation, showed hypomethylated DMRs and were upregulated. Expression of the antioxidant geneNQO1was upregulated, with a hypomethylated DMR. The DMR containing cancer‐relatedMIR21was hypomethylated in advanced NAFLD.Conclusions: Co‐methylation and DMR analyses suggest that the NAFLD liver undergoes mitochondrial dysfunction, decreased lipid metabolism, and impaired oxidoreductase activity, and acquires tumorigenic potential at the epigenetic level.
Funding Information
  • Japan Society for the Promotion of Science (16K09781, 25461343, 26460999, 26870290)

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