Epigenetics in liver disease: from biology to therapeutics

Abstract

Knowledge of the fundamental epigenetic mechanisms governing gene expression and cellular phenotype are sufficiently advanced that novel insights into the epigenetic control of chronic liver disease are now emerging. Hepatologists are in the process of shedding light on the roles played by DNA methylation, histone/chromatin modifications and non-coding RNAs in specific liver pathologies. Alongside these discoveries are advances in the technologies for the detection and quantification of epigenetic biomarkers, either directly from patient tissue or from body fluids. The premise for this review is to survey the recent advances in the field of liver epigenetics and to explore their potential for translation by industry and clinical hepatologists for the design of novel therapeutics and diagnostic/prognostic biomarkers. In particular, we present findings in the context of hepatocellular carcinoma, fibrosis and non-alcoholic fatty liver disease, where there is urgent unmet need for new clinical interventions and biomarkers.

Hepatic stellate cells as key target in liver fibrosis

“…Global epigenomic and local epigenetic transcriptional dysregulation in HSC can occur as response or adaptation to environmental and/or etiological stressors, and has been implicated in its fibrogenic activation [254]. …”

To die or not to die: death signaling in nonalcoholic fatty liver disease

“…They include DNA methylation, altered expression of non-coding RNAs, histone modification, and chromatin remodeling [102, 103]. Epigenetic changes can be reversed by interventional approaches [104], raising clinical interest in this area [105–107].…”

Dual Targeting of Histone Methyltransferase G9a and DNA‐Methyltransferase 1 for the Treatment of Experimental Hepatocellular Carcinoma

“…This is accompanied by locus‐specific hypermethylation and silencing of putative tumor suppressor genes in association with abnormal expression of the DNA methyltransferases DNMT1, DNMT3a, and DNMT3b . These alterations contribute to the pathogenesis and prognosis of HCC from early stages of the disease, and targeting aberrant DNA methylation using DNMT inhibitors is currently being explored . Other epigenetic alterations found in HCC include reversible changes in the posttranslational modification of histones, such as acetylation or methylation of lysine residues, which may occur in genome‐wide and gene‐specific manners .…”