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Series GSE34423 Query DataSets for GSE34423
Status Public on Dec 14, 2011
Title Phenobarbital mediates an epigenetic switch at the constitutive androstane receptor (CAR) target gene Cyp2b10 in the liver of B6C3F1 mice [Expression array].
Organism Mus musculus
Experiment type Expression profiling by array
Summary Evidence suggests that epigenetic perturbations are involved in the adverse effects associated with some drugs and toxicants, including certain classes of non-genotoxic carcinogens. Such epigenetic changes (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 of non-genotoxic liver carcinogenesis. Methylated DNA Immunoprecipitation (MeDIP)-coupled microarray profiling of 17,967 promoter regions and 4,566 intergenic CpG islands was combined with genome-wide mRNA expression profiling to identify liver tissue-specific PB-mediated DNA methylation and transcriptional alterations. Only a limited number of significant anti-correlations were observed between PB-induced transcriptional and promoter-based DNA methylation perturbations. However, the constitutive androstane receptor (CAR) target gene Cyp2b10 was found to be concomitantly hypomethylated and transcriptionally activated in a liver tissue-specific manner following PB treatment. Furthermore, analysis of active and repressive histone modifications using chromatin immunoprecipitation revealed a strong PB-mediated epigenetic switch at the Cyp2b10 promoter. Our data reveal that PB-induced transcriptional perturbations are not generally associated with broad changes in the DNA methylation status at proximal promoters and suggest that the drug-inducible CAR pathway regulates an epigenetic switch from repressive to active chromatin at the target gene Cyp2b10. This study demonstrates the utility of integrated epigenomic and transcriptomic profiling for elucidating early mechanisms and biomarkers of non-genotoxic carcinogenesis.
 
Overall design 29–32 days old male B6C3F1/Crl (C57BL/6 ♂ x C3H/He ♀) mice were obtained from Charles River Laboratories (Germany). Animals were allowed to acclimatise for 5 days prior to being randomly divided into two treatment groups (n = 10) and phenobarbital (Sigma 04710, 0.05% (w/v) in drinking water) was administered to one group through ad libitum access to drinking water for 28 days. Mice were checked daily for activity and behavior and sacrificed on the last day of dosing (day 28). Blood was withdrawn for PK analysis and target (liver) and non-target (kidney) tissues removed, split into several sections, frozen in liquid nitrogen and stored at −80°C for subsequent analyses. Total RNA from liver and kidney was purified and processed for Affymetrix gene expression profiling while genomic DNA was prepared for promoter array based methylome analysis using the Methylated DNA immunoprecipitation (MeDIP) procedure. Remaining tissue material was used for chromatin immunoprecipitation (ChIP) to analyze histone modifications at individual promoters. Plasma samples were also collected to evaluate phenobarbital exposure in individual animals by LC-MS.
 
Contributor(s) Lempiäinen H, Müller A, Brasa S, Teo S, Roloff T, Morawiec L, Zamurovic N, Vicart A, Funhoff E, Couttet P, Schübeler D, Grenet O, Marlowe J, Moggs J, Terranova R
Citation(s) 21455306
Submission date Dec 13, 2011
Last update date Feb 11, 2019
Contact name Jonathan Moggs
E-mail jonathan.moggs@novartis.com
Organization name Novartis
Street address Fabrikstrasse 2
City Basel
ZIP/Postal code 4056
Country Switzerland
 
Platforms (1)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
Samples (40)
GSM848818 PB_Kidney_Control_5
GSM848819 PB_Kidney_Control_1
GSM848820 PB_Kidney_Control_9
This SubSeries is part of SuperSeries:
GSE34463 Phenobarbital mediates an epigenetic switch at the constitutive androstane receptor (CAR) target gene Cyp2b10 in the liver of B6C3F1 mice.
GSE68387 IMI MARCAR Project: towards novel biomarkers for cancer risk assessment
Relations
BioProject PRJNA156385

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SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE34423_RAW.tar 141.7 Mb (http)(custom) TAR (of CEL)
Raw data provided as supplementary file
Processed data included within Sample table

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