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Characterization of drug-induced transcriptional modules: towards drug repositioning and functional understanding

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Official URL:https://doi.org/10.1038/msb.2013.20
PubMed:View item in PubMed
Creators Name:Iskar, M. and Zeller, G. and Blattmann, P. and Campillos, M. and Kuhn, M. and Kaminska, K.H. and Runz, H. and Gavin, A.C. and Pepperkok, R. and van Noort, V. and Bork, P.
Journal Title:Molecular Systems Biology
Journal Abbreviation:Mol Syst Biol
Volume:9
Page Range:662
Date:2013
Keywords:Cell Line Models in Drug Discovery, Drug-Induced Transcriptional Modules, Drug Repositioning, Gene Function Prediction, Transcriptome Conservation across Cell Types and Organisms, Animals, Rats
Abstract:In pharmacology, it is crucial to understand the complex biological responses that drugs elicit in the human organism and how well they can be inferred from model organisms. We therefore identified a large set of drug-induced transcriptional modules from genome-wide microarray data of drug-treated human cell lines and rat liver, and first characterized their conservation. Over 70% of these modules were common for multiple cell lines and 15% were conserved between the human in vitro and the rat in vivo system. We then illustrate the utility of conserved and cell-type-specific drug-induced modules by predicting and experimentally validating (i) gene functions, e.g., 10 novel regulators of cellular cholesterol homeostasis and (ii) new mechanisms of action for existing drugs, thereby providing a starting point for drug repositioning, e.g., novel cell cycle inhibitors and new modulators of alpha-adrenergic receptor, peroxisome proliferator-activated receptor and estrogen receptor. Taken together, the identified modules reveal the conservation of transcriptional responses towards drugs across cell types and organisms, and improve our understanding of both the molecular basis of drug action and human biology.
ISSN:1744-4292
Publisher:Nature Publishing Group (U.K.)
Item Type:Article

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