Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome.
Genome Biol, 2012/10/03;13(10):R93.
Thomson JP, Lempiäinen H, Hackett JA, Nestor CE, Müller A, Bolognani F, Oakeley EJ, Schübeler D, Terranova R, Reinhardt D, Moggs JG, Meehan RR
PMID: 23034186DOI: 10.1186/gb-2012-13-10-r93
Impact factor: 17.906
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.
MeSH terms
5-Methylcytosine; Animals; Cytosine; DNA Methylation; Epigenomics; Gene Expression Profiling; Gene Expression Regulation; Histones; Liver; Male; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Phenobarbital; Promoter Regions, Genetic
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