Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome

John P Thomson, Harri Lempiäinen, Jamie A Hackett, Colm E Nestor, Arne Müller, Federico Bolognani, Edward J Oakeley, Dirk Schübeler, Rémi Terranova, Diana Reinhardt, Jonathan G Moggs, Richard Meehan

Research output: Contribution to journalArticlepeer-review

Abstract

ABSTRACT: BACKGROUND: 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.

RESULTS: 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.

CONCLUSIONS: 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.
Original languageEnglish
Article numberR93
JournalGenome Biology
Volume13
Issue number10
DOIs
Publication statusPublished - 3 Oct 2012

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