Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome
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Thomson, John P, Lempiaeinen, Harri, Hackett, Jamie, Nestor, Colm E, Mueller, Arne, Bolognani, Federico, Oakeley, Edward James, Schuebeler, Dirk, Terranova, Remi, Rheinhardt, Diana, Moggs, Jonathan and Meehan, Richard R (2012) Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome. Genome Biology, 13 (10). R93. ISSN 1465-6906
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.
| Item Type: | Article |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/6077 |