title: Inferring statin-induced gene regulatory relationships in primary human hepatocytes.
abstract: BACKGROUND
  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.
  
  
  BACKGROUND
  Microarray data are available at the Gene Expression Omnibus (GEO) database at www.ncbi.nlm.nih.gov/geo/, under accession number GSE29868.
  
  
  BACKGROUND
  andreas.zell@uni-tuebingen.de; adrian.schroeder@uni-tuebingen.de
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Center for Bioinformatics Tuebingen, University of Tuebingen, Tuebingen, Germany. adrian.schroeder@uni-tuebingen.de
authors.forename: Adrian
authors.initials: A
authors.lastname: Schröder
authors.forename: Johannes
authors.initials: J
authors.lastname: Wollnik
authors.forename: Clemens
authors.initials: C
authors.lastname: Wrzodek
authors.forename: Andreas
authors.initials: A
authors.lastname: Dräger
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.forename: Oliver
authors.initials: O
authors.lastname: Burk
authors.forename: Maria
authors.initials: M
authors.lastname: Thomas
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.forename: Andreas
authors.initials: A
authors.lastname: Zell
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology; D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005809:Genes, Regulator / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D011485:Protein Binding; D011758:Pyrroles / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D014157:Transcription Factors; D012313:RNA; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D051544:Cytochrome P-450 CYP3A