Epigenetic Biomarkers for the Diagnosis and Treatment of Liver Disease

Abstract

Research in the last decades has demonstrated the relevance of epigenetics in controlling gene expression to maintain cell homeostasis, and the important role played by epigenome alterations in disease development. Moreover, the reversibility of epigenetic marks can be harnessed as a therapeutic strategy, and epigenetic marks can be used as diagnosis biomarkers. Epigenetic alterations in DNA methylation, histone post-translational modifications (PTMs), and non-coding RNA (ncRNA) expression have been associated with the process of hepatocarcinogenesis. Here, we summarize epigenetic alterations involved in the pathogenesis of chronic liver disease (CLD), particularly focusing on DNA methylation. We also discuss their utility as epigenetic biomarkers in liquid biopsy for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Finally, we discuss the potential of epigenetic therapeutic strategies for HCC treatment.

Keywords: DNA methylation; epidrugs; hepatocellular carcinoma; liquid biopsy; liver fibrosis; precision medicine.

Figure 1

Epigenetic mechanisms control open and closed chromatin states, contributing to regulate gene expression. This drawing represents epigenetic changes described in the progression of chronic liver disease (see main text) such as DNA hypermethylation of tumor suppressor genes and histone acetylation of oncogenes. These changes are associated with the activity of different epigenetic modifiers, including histone methyltransferases (HMTs), histone demethylases (HDMs), histone acetyltransferases (HATs), histone deacetylases (HDACs), DNA methyltransferases (DNMTs), the ten-eleven-translocation (TETs) family of methyl-DNA dioxygenases, and the readers bromodomain-containing protein 4 (BRD4) and methyl-CpG-binding protein 2 (MeCP2). These enzymes and protein adaptors add, remove, or read the epigenetic marks representing new therapeutic targets for a variety of inhibitors known as epidrugs.

Figure 2

The epigenetically marked DNA and chromatin are released from the damaged liver to the bloodstream. Therefore, the identification of disease-specific epigenetic biomarkers in the plasma or liquid biopsy represents a non-invasive tool for the early detection of fibrosis or diagnosis of HCC and the prognosis and therapeutic guidance of patients.