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Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome
University of Edinburgh, Western General Hospital, UK .
Novartis Institute for Biomedical Research, Basel, Switzerland .
University of Edinburgh, Western General Hospital, UK.
University of Edinburgh, Western General Hospital, Edinburgh, UK.
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2012 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 13, no 10Article in journal (Refereed) Published
Abstract [en]

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.


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.

Place, publisher, year, edition, pages
BioMed Central, 2012. Vol. 13, no 10
National Category
URN: urn:nbn:se:liu:diva-100011DOI: 10.1186/gb-2012-13-10-r93ISI: 000313183900012PubMedID: 23034186ScopusID: 2-s2.0-84866847877OAI: diva2:659354
Available from: 2013-10-25 Created: 2013-10-25 Last updated: 2015-11-11Bibliographically approved

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