期刊
GENOME BIOLOGY
卷 13, 期 10, 页码 -出版社
BMC
DOI: 10.1186/gb-2012-13-10-R93
关键词
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资金
- Innovative Medicine Initiative Joint Undertaking (IMI JU) [115001]
- Novartis
- IMI-MARCAR at MRC HGU
- Medical Research Council
- Breakthrough Breast Cancer (BBC)
- IMI-MARCAR
- MRC
- BBSRC
- BBC
- NIBR
- MRC [MC_PC_U127574433, MC_U127574433] Funding Source: UKRI
- Medical Research Council [MC_PC_U127574433, MC_U127574433] Funding Source: researchfish
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.
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