Drug induced changes in the mouse liver epigenome

Epigenetic reprogramming involves the erasure and re-establishment of DNA and chromatin modifications during mammalian development. Once re-established the epigenome contributes to the maintenance of tissue identity. Perturbations in the epigenome are associated with exposure to a range of drugs and toxicants, including non-genotoxic carcinogens. Application of genome-wide integrated epigenomic and transcriptomic studies reveals the extent and dynamic nature of epigenetic perturbations resulting from xenobiotic exposure. We have demonstrated that exposure to the drug phenobarbital (PB) perturbs normal 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles in a dose dependent manner. The PB response gene Cyp2b10 undergoes a rapid transcriptional activation alongside a parallel active demethylation (5mC > 5hmC > C) event at its promoter region. We observe numerous changes in the two DNA modifications, which are dynamic and reciprocal in nature, with frequent losses in 5hmC observed at and around the transcriptional start sites of many genes. Dynamic changes in promoter 5hmC and 5mC can be related to a global response to PB exposure that is independent of transcriptional changes and links with cancer associated DNA modification reprogramming profiles. Our study illustrates the potential for 5mC/5hmC profiling at promoter regions to identify potential drivers of non-genotoxic carcinogenesis in the mouse liver. Drug-induced perturbations of the epigenome generate unique epigenetic signatures that can enhance our mechanistic understanding of xenobiotic exposure, and potentially lead to the identification of novel safety biomarkers.