Phenobarbital Mediates an Epigenetic Switch at the Constitutive Androstane Receptor (CAR) Target Gene Cyp2b10 in the Liver of B6C3F1 Mice
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Terranova, Remi (2011) Phenobarbital Mediates an Epigenetic Switch at the Constitutive Androstane Receptor (CAR) Target Gene Cyp2b10 in the Liver of B6C3F1 Mice. PLoS ONE, 6 (3). e118216-e18216. ISSN 1932-6203
Abstract
Evidence suggests that epigenetic perturbations are involved in the adverse effects associated with some drugs and toxicants, including certain classes of non-genotoxic carcinogens. Epigenetic aberrations (altered DNA methylation and covalent histone modifications) may take place at the earliest stages of carcinogenesis and their identification holds great promise for biomedical research.
Here we evaluate the sensitivity and specificity of genome-wide epigenomic and transcriptomic profiling in phenobarbital (PB)-treated B6C3F1 mice, a well-characterized rodent model for non-genotoxic liver carcinogenesis. 4 weeks of PB treatment lead to significant, tissue-specific, PB-mediated transcriptional alterations using expression microarrays and tissue-specific DNA methylation perturbations by MeDIP-array profiling of 17,967 promoter regions and 4,566 intergenic CpG islands. These results showed very limited number of significant anti-correlations between transcriptional and promoter-based DNA methylation perturbations in both liver and kidney yet identified the constitutive androstane receptor (CAR)/pregnane X receptor (PXR) target gene Cyp2b10 as methylated and repressed in untreated liver and hypomethylated and highly expressed following PB treatment. In kidney, Cyp2b10 promoter methylation and gene expression remained unaffected. Furthermore, analysis of active and repressive histone modifications using chromatin immunoprecipitation revealed a strong PB-mediated epigenetic switch at the Cyp2b10 promoter.
Our integrated genome-wide profiling data show that PB-induced transcriptional perturbations are generally not linked with broad changes in the DNA methylation status at proximal promoters and suggest a novel function for the drug-inducible CAR/PXR pathway in regulating chromatin architecture of selected target genes. These data support the emerging role of epigenomic profiling in better understanding of mechanisms and identification of biomarkers of non-genotoxic carcinogenesis and in improving drug safety assessment.
| Item Type: | Article |
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| Date Deposited: | 13 Oct 2015 13:15 |
| Last Modified: | 13 Oct 2015 13:15 |
| URI: | https://oak.novartis.com/id/eprint/3703 |