This article is part of a special issue on epigenomics.
Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome
1 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
2 Investigative Toxicology, Preclinical Safety, Translational Sciences, Novartis Institute for Biomedical Research, Lichtstrasse 35, CH-4057 Basel, Switzerland
3 Breakthrough Breast Cancer Research Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
4 Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland
5 Biomarker Development, Human Genetics and Genomics, Translational Sciences, Novartis Institutes for Biomedical Research, Maulbeerstrasse 66, 4056 Basel, Switzerland
6 Member of MARCAR consortium
Genome Biology 2012, 13:R93 doi:10.1186/gb-2012-13-10-r93Published: 3 October 2012
Induction and promotion of liver cancer by exposure to non-genotoxic carcinogens coincides with epigenetic perturbations, including specific changes in DNA methylation. Here we investigate the genome-wide dynamics of 5-hydroxymethylcytosine (5hmC) as a likely intermediate of 5-methylcytosine (5mC) demethylation in a DNA methylation reprogramming pathway. We use a rodent model of non-genotoxic carcinogen exposure using the drug phenobarbital.
Exposure to phenobarbital results in dynamic and reciprocal changes to the 5mC/5hmC patterns over the promoter regions of a cohort of genes that are transcriptionally upregulated. This reprogramming of 5mC/5hmC coincides with characteristic changes in the histone marks H3K4me2, H3K27me3 and H3K36me3. Quantitative analysis of phenobarbital-induced genes that are involved in xenobiotic metabolism reveals that both DNA modifications are lost at the transcription start site, while there is a reciprocal relationship between increasing levels of 5hmC and loss of 5mC at regions immediately adjacent to core promoters.
Collectively, these experiments support the hypothesis that 5hmC is a potential intermediate in a demethylation pathway and reveal precise perturbations of the mouse liver DNA methylome and hydroxymethylome upon exposure to a rodent hepatocarcinogen.