Chemical carcinogenesis and epigenetics

Gene expression in higher eukaryotes is controlled in part by a complex series of chemical modifications to DNA and associated histone proteins that alter the condensation of chromatin and accessibility of genes for transcription. The transcriptional silencing of tumor suppressor genes or the inappropriate activation of transforming genes is a hallmark of human tumors and, in many cases, can be attributed to the perturbation of epigenetic signals. In this review, we provide a brief introduction to epigenetic gene control with a focus on molecular events and, in particular, the role of 5-methylcytosine (5mC) in DNA on epigenetic programming. The mechanisms by which enzymatic methylation alters DNA-protein interactions and methylase activity are described. The conversion of cytosine to 5mC changes the chemistry of the base and, in some cases, the surrounding DNA as well. We describe how carcinogens can modify epigenetic patterns through chemical interactions with cytosine and 5mC. Emerging evidence also suggests that chemical damage to DNA can alter interactions with methyltransferases and proteins containing a methyl-binding domain, resulting in heritable changes in epigenetic signals.