DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease

Abstract

BackgroundChronic hepatitis B infection is characterized by hepatic immune and inflammatory response with considerable variation in the rates of progression to cirrhosis. Genetic variants and environmental cues influence predisposition to the development of chronic liver disease; however, it remains unknown if aberrant DNA methylation is associated with fibrosis progression in chronic hepatitis B.ResultsTo identify epigenetic marks associated with inflammatory and fibrotic processes of the hepatitis B-induced chronic liver disease, we carried out hepatic genome-wide methylation profiling using Illumina Infinium BeadArrays comparing mild and severe fibrotic disease in a discovery cohort of 29 patients. We obtained 310 differentially methylated regions and selected four loci comprising three genes from the top differentially methylated regions: hypermethylation of HOXA2 and HDAC4 along with hypomethylation of PPP1R18 were significantly linked to severe fibrosis. We replicated the prominent methylation marks in an independent cohort of 102 patients by bisulfite modification and pyrosequencing. The timing and causal relationship of epigenetic modifications with disease severity was further investigated using a cohort of patients with serial biopsies.ConclusionsOur findings suggest a linkage of widespread epigenetic dysregulation with disease progression in chronic hepatitis B infection. CpG methylation at novel genes sheds light on new molecular pathways, which can be potentially exploited as a biomarker or targeted to attenuate inflammation and fibrosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0218-1) contains supplementary material, which is available to authorized users.

DNA methylation signatures of illicit drug injection and hepatitis C are associated with HIV frailty

“…Genes involved in immunity and inflammation are logical candidates for the convergent epigenetic effects of IDU. DNA methylation (DNA-me), one of the major epigenetic mechanisms, generally suppresses, while demethylation generally increases, gene transcription, and both play important roles in inflammatory processes associated with cardiovascular disease, cancer, and infectious disease 12 – 18 . We recently reported that the methylation of genes in immune and inflammation domains in white blood cells (WBC) differed significantly between HIV-infected and uninfected individuals 19 .…”

Epigenetic Biomarkers for the Diagnosis and Treatment of Liver Disease

“…Both genome-wide hypomethylation and region-specific hypermethylation are present not only in HCC but also in preneoplastic conditions [ 51 , 52 , 53 ]. Moreover, CpG methylation signatures have been associated with the progression of HVB-related liver disease [ 54 ], NAFLD fibrosis [ 55 , 56 ] and cirrhosis [ 57 ], and the poor survival of HCC patients [ 58 ]. DNA methylation changes repressing hepatic HNF4A-dependent gene expression have been associated with the loss of hepatocellular functions observed in patients with alcoholic hepatitis [ 59 ].…”

New perspectives of biomarkers for the management of chronic hepatitis B

“…Recently, through hepatic genome-wide methylation profiling, hypermethylation of HOXA2 and HDAC4 along with hypomethylation of PPP1R18 were identified and significantly linked to severe fibrosis in patients with CHB. cytosine-guanine dinucleotide methylation within HOXA2, PPP1R18 and HDAC4 genes might serve as genetic markers for progression of CHB [ 81 ].…”