Comparative analysis of acute and chronic corticosteroid pharmacogenomic effects in rat liver: transcriptional dynamics and regulatory structures.
BACKGROUND
Comprehensively understanding corticosteroid pharmacogenomic effects is an essential step towards an insight into the underlying molecular mechanisms for both beneficial and detrimental clinical effects. Nevertheless, even in a single tissue different methods of corticosteroid administration can induce different patterns of expression and regulatory control structures. Therefore, rich in vivo datasets of pharmacological time-series with two dosing regimens sampled from rat liver are examined for temporal patterns of changes in gene expression and their regulatory commonalities.


RESULTS
The study addresses two issues, including (1) identifying significant transcriptional modules coupled with dynamic expression patterns and (2) predicting relevant common transcriptional controls to better understand the underlying mechanisms of corticosteroid adverse effects. Following the orientation of meta-analysis, an extended computational approach that explores the concept of agreement matrix from consensus clustering has been proposed with the aims of identifying gene clusters that share common expression patterns across multiple dosing regimens as well as handling challenges in the analysis of microarray data from heterogeneous sources, e.g. different platforms and time-grids in this study. Six significant transcriptional modules coupled with typical patterns of expression have been identified. Functional analysis reveals that virtually all enriched functions (gene ontologies, pathways) in these modules are shown to be related to metabolic processes, implying the importance of these modules in adverse effects under the administration of corticosteroids. Relevant putative transcriptional regulators (e.g. RXRF, FKHD, SP1F) are also predicted to provide another source of information towards better understanding the complexities of expression patterns and the underlying regulatory mechanisms of those modules.


CONCLUSIONS
We have proposed a framework to identify significant coexpressed clusters of genes across multiple conditions experimented from different microarray platforms, time-grids, and also tissues if applicable. Analysis on rich in vivo datasets of corticosteroid time-series yielded significant insights into the pharmacogenomic effects of corticosteroids, especially the relevance to metabolic side-effects. This has been illustrated through enriched metabolic functions in those transcriptional modules and the presence of GRE binding motifs in those enriched pathways, providing significant modules for further analysis on pharmacogenomic corticosteroid effects.
BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, New Jersey, USA.
Tung T
TT
Nguyen
Richard R
RR
Almon
Debra C
DC
Dubois
William J
WJ
Jusko
Ioannis P
IP
Androulakis
D000818:Animals; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D010597:Pharmacogenetics; D051381:Rats; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
D005938:Glucocorticoids; D014157:Transcription Factors