DNA methylation in hepatocellular carcinoma: what is the use?

Department of Hepatology, University Hospitals Leuven & Department of Clinical & Experimental Medicine, KU Leuven, Herestraat 49, 3000 Leuven, Belgium *Author for correspondence: jeroen.dekervel@med.kuleuven.be Epigenetics are heritable changes in gene expression that occur without changes in DNA sequence [1]. In this editorial we will focus on DNA methylation, the most studied form of epigenetic regulation in cancers of the liver. DNA methylation usually takes place at 5 position of the cytosine ring (resulting in 5mC) within CpG dinucleotides. These dinucleotides are relatively rare and unequally distributed throughout the genome. For example, 60% of human genes have a cluster of CpGs or so called ‘CpG island (CGI)’ in their regulatory region [2]. Methylation of a CGI results in transcriptional silencing of the associated gene. Other genomic regions with high CpG density include repetitive genomic sequences such as centromeres where DNA methylation guards chromosome stability. In a differentiated human cell, CpG islands are mostly unmethylated facilitating expression of the associated gene, whereas the baseline methylation of repetitive sequences prevents mitotic recombinations such as deletions or translocations [3]. DNA methylation, a process catalyzed by DNA methyltransferases, occurs nearly always symmetrical in both the top and bottom strands [4]. This enables propagation of methylation across cell divisions conform the heritable nature of epigenetics as stated in the definition. More recently, it has become clear that DNA undergoes active demethylation as well, regulated by the ten-eleven translocation (TET) family of proteins. These enzymes produce an intermediate, 5-hydroxymethylcytosine or 5hmC, which ultimately leads to unmethylated cytosine [5].