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Alterations of DNA methylation are among the most consistent epigenetic changes observed in human cancers. In comparison with normal liver tissue, such alterations occur in a genome-wide manner in non-cancerous liver tissue showing chronic hepatitis or cirrhosis, which are widely considered to be precancerous conditions. DNA methylation alterations at the precancerous stage may rapidly generate more malignant cancers. Multiple tumor-related genes, such as the E-cadherin, HIC-1, p16, p15, TMS1/ASC, TIMP3, MGMT, RASSF1A 1, 14-3-3-σ, and SOCS-1 genes, are silenced by DNA hypermethylation in hepatocellular carcinomas (HCCs). Expression of DNA methyltransferase (DNMT) 1 is significantly higher in non-cancerous liver tissue showing chronic hepatitis or cirrhosis than in normal liver tissue. DNMT1 overexpression is also correlated with poorer tumor differentiation, portal vein involvement and intrahepatic metastasis of HCCs, and poorer patient outcome. On the other hand, overexpression of DNMT3b4, an inactive splice variant of DNMT3b, may lead to chromosomal instability through induction of DNA hypomethylation in pericentromeric satellite regions during hepatocarcinogenesis. Genome-wide DNA methylation profiling provides optimal indicators for carcinogenetic risk estimation in patients with chronic liver diseases, and for prognostication in patients with HCCs. With the intention of controlling hepatocarcinogenesis from the chronic liver disease stage, translational epigenetics have come of age. [ABSTRACT FROM AUTHOR]

The control of transcription initiation in mammalian cells can be very broadly divided into three categories: intrinsic promoter strength and availability of core transcription machinery (Dvir et al. 2001, Sandelin 2007), the actions of promoter- or regulon-specific transcription factors (positive and negative) (e.g., (Malik and Roeder 2005, Hoffmann et al. 2006)), and the control of DNA accessibility by altering chromatin structure (Li et al. 2007, Berger 2007). This latter category, including posttranslational modifications to histones and postreplicational modification of DNA, is in many ways less well-understood than the other two. Nucleosomes are the fundamental building blocks of eukaryotic chromatin, and consist of ∼146 base pairs of DNA wrapped twice around a histone octamer (Luger et al. 1997). A variety of protein-modifying enzymes (including methyltransferases, MTases) is responsible for histone modification, primarily at their flexible N-termini (Shilatifard 2006, Shi 2007, Bhaumik 2007). We will touch on the functional links between histone modification and that of DNA, but the purpose of this chapter is to summarize, from a structural perspective, the rapidly-growing body of information about the proteins that methylate mammalian DNA. [ABSTRACT FROM AUTHOR]