Abstract (Expand)
MOTIVATION: Statins are the most widely used cholesterol-lowering drugs. The primary target of statins is HMG-CoA reductase, a key enzyme in cholesterol synthesis. However, statins elicit pleitropic … responses including beneficial as well as adverse effects in the liver or other organs. Today, the regulatory mechanisms that cause these pleiotropic effects are not sufficiently understood. RESULTS: In this work, genome-wide RNA expression changes in primary human hepatocytes of six individuals were measured at up to six time points upon atorvastatin treatment. A computational analysis workflow was applied to reconstruct regulatory mechanisms based on these drug-response data and available knowledge about transcription factor (TF) binding specificities and protein-drug interactions. Several previously unknown TFs were predicted to be involved in atorvastatin-responsive gene expression. The novel relationships of nuclear receptors NR2C2 and PPARA on CYP3A4 were successfully validated in wet-lab experiments. AVAILABILITY: Microarray data are available at the Gene Expression Omnibus (GEO) database at www.ncbi.nlm.nih.gov/geo/, under accession number GSE29868. CONTACT: andreas.zell@uni-tuebingen.de; adrian.schroeder@uni-tuebingen.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Authors: A. Schroder, J. Wollnik, C. Wrzodek, A. Drager, M. Bonin, O. Burk, M. Thomas, W. E. Thasler, U. M. Zanger, A. Zell
Date Published: 14th Jul 2011
Publication Type: Not specified
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