{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T02:29:17Z","timestamp":1759026557787,"version":"3.38.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"18","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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.<\/jats:p><jats:p>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\u2013response data and available knowledge about transcription factor (TF) binding specificities and protein\u2013drug 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.<\/jats:p><jats:p>Availability: Microarray data are available at the Gene Expression Omnibus (GEO) database at www.ncbi.nlm.nih.gov\/geo\/, under accession number GSE29868.<\/jats:p><jats:p>Contact: \u00a0andreas.zell@uni-tuebingen.de; adrian.schroeder@uni-tuebingen.de<\/jats:p><jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btr416","type":"journal-article","created":{"date-parts":[[2011,7,15]],"date-time":"2011-07-15T00:34:59Z","timestamp":1310690099000},"page":"2473-2477","source":"Crossref","is-referenced-by-count":14,"title":["Inferring statin-induced gene regulatory relationships in primary human hepatocytes"],"prefix":"10.1093","volume":"27","author":[{"given":"Adrian","family":"Schr\u00f6der","sequence":"first","affiliation":[{"name":"1 Center for Bioinformatics Tuebingen (ZBIT), 2Department of Medical Genetics, Microarray Facility, University of Tuebingen, Tuebingen, 3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and 4Department of Surgery, Grosshadern Hospital, Ludwig-Maximilians-University Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Wollnik","sequence":"additional","affiliation":[{"name":"1 Center for Bioinformatics Tuebingen (ZBIT), 2Department of Medical Genetics, Microarray Facility, University of Tuebingen, Tuebingen, 3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and 4Department of Surgery, Grosshadern Hospital, Ludwig-Maximilians-University Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clemens","family":"Wrzodek","sequence":"additional","affiliation":[{"name":"1 Center for Bioinformatics Tuebingen (ZBIT), 2Department of Medical Genetics, Microarray Facility, University of Tuebingen, Tuebingen, 3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and 4Department of Surgery, Grosshadern Hospital, Ludwig-Maximilians-University Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Dr\u00e4ger","sequence":"additional","affiliation":[{"name":"1 Center for Bioinformatics Tuebingen (ZBIT), 2Department of Medical Genetics, Microarray Facility, University of Tuebingen, Tuebingen, 3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and 4Department of Surgery, Grosshadern Hospital, Ludwig-Maximilians-University Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Bonin","sequence":"additional","affiliation":[{"name":"1 Center for Bioinformatics Tuebingen (ZBIT), 2Department of Medical Genetics, Microarray Facility, University of Tuebingen, Tuebingen, 3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and 4Department of Surgery, Grosshadern Hospital, Ludwig-Maximilians-University Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver","family":"Burk","sequence":"additional","affiliation":[{"name":"1 Center for Bioinformatics Tuebingen (ZBIT), 2Department of Medical Genetics, Microarray Facility, University of Tuebingen, Tuebingen, 3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and 4Department of Surgery, Grosshadern Hospital, Ludwig-Maximilians-University Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Thomas","sequence":"additional","affiliation":[{"name":"1 Center for Bioinformatics Tuebingen (ZBIT), 2Department of Medical Genetics, Microarray Facility, University of Tuebingen, Tuebingen, 3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and 4Department of Surgery, Grosshadern Hospital, Ludwig-Maximilians-University Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang E.","family":"Thasler","sequence":"additional","affiliation":[{"name":"1 Center for Bioinformatics Tuebingen (ZBIT), 2Department of Medical Genetics, Microarray Facility, University of Tuebingen, Tuebingen, 3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and 4Department of Surgery, Grosshadern Hospital, Ludwig-Maximilians-University Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich M.","family":"Zanger","sequence":"additional","affiliation":[{"name":"1 Center for Bioinformatics Tuebingen (ZBIT), 2Department of Medical Genetics, Microarray Facility, University of Tuebingen, Tuebingen, 3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and 4Department of Surgery, Grosshadern Hospital, Ludwig-Maximilians-University Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Zell","sequence":"additional","affiliation":[{"name":"1 Center for Bioinformatics Tuebingen (ZBIT), 2Department of Medical Genetics, Microarray Facility, University of Tuebingen, Tuebingen, 3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and 4Department of Surgery, Grosshadern Hospital, Ludwig-Maximilians-University Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2011,7,14]]},"reference":[{"key":"2023012512001202100_B1","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.1093\/bioinformatics\/bth179","article-title":"A genetic algorithm for the detection of new cis-regulatory modules in sets of coregulated genes","volume":"20","author":"Aerts","year":"2004","journal-title":"Bioinformatics"},{"key":"2023012512001202100_B2","doi-asserted-by":"crossref","first-page":"622","DOI":"10.7150\/ijbs.5.622","article-title":"Kr\u00fcppel-like family of transcription factors: an emerging new frontier in fat biology","volume":"5","author":"Brey","year":"2009","journal-title":"Int. J. Biol. Sci."},{"key":"2023012512001202100_B3","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1111\/j.1742-1241.2008.01884.x","article-title":"Statin safety and chronic liver disease","volume":"62","author":"Cash","year":"2008","journal-title":"Int. J. Clin. Pract."},{"key":"2023012512001202100_B4","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1194\/jlr.R900012-JLR200","article-title":"Bile acid transporters","volume":"50","author":"Dawson","year":"2009","journal-title":"J. Lipid Res."},{"key":"2023012512001202100_B5","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1016\/j.bcp.2007.07.040","article-title":"Regulation of cyp3a4 and cyp2b6 expression by liver x receptor agonists","volume":"74","author":"Duniec-Dmuchowski","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"2023012512001202100_B6","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1124\/dmd.110.033886","article-title":"Profiling induction of cytochrome p450 enzyme activity by statins using a new liquid chromatography-tandem mass spectrometry cocktail assay in human hepatocytes","volume":"38","author":"Feidt","year":"2010","journal-title":"Drug Metab. Dispos."},{"key":"2023012512001202100_B7","doi-asserted-by":"crossref","first-page":"14581","DOI":"10.1074\/jbc.M010173200","article-title":"Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin","volume":"276","author":"Geick","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2023012512001202100_B8","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/978-0-387-77240-0","article-title":"Hypergeometric testing used for gene set enrichment analysis","volume-title":"Bioconductor Case Studies","author":"Hahne","year":"2008"},{"key":"2023012512001202100_B9","first-page":"3940","article-title":"The muscle-specific ubiquitin ligase atrogin-1\/mafbx mediates statin-induced muscle toxicity","volume":"117","author":"Hanai","year":"2007","journal-title":"J. Clin. Invest."},{"key":"2023012512001202100_B10","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1016\/S0090-9556(24)15086-6","article-title":"Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-coa reductase inhibitor atorvastatin","volume":"28","author":"Jacobsen","year":"2000","journal-title":"Drug Metab. Dispos."},{"key":"2023012512001202100_B11","doi-asserted-by":"crossref","first-page":"D412","DOI":"10.1093\/nar\/gkn760","article-title":"String 8\u2013a global view on proteins and their functional interactions in 630 organisms","volume":"37","author":"Jensen","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2023012512001202100_B12","doi-asserted-by":"crossref","first-page":"3576","DOI":"10.1093\/nar\/gkg585","article-title":"MATCHTM: a tool for searching transcription factor binding sites in DNA sequences","volume":"31","author":"Kel","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"2023012512001202100_B13","doi-asserted-by":"crossref","first-page":"D552","DOI":"10.1093\/nar\/gkp937","article-title":"Stitch 2: an interaction network database for small molecules and proteins","volume":"38","author":"Kuhn","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2023012512001202100_B14","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1146\/annurev.pharmtox.45.120403.095748","article-title":"Pleiotropic effects of statins","volume":"45","author":"Liao","year":"2005","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"2023012512001202100_B15","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1158\/0008-5472.CAN-07-5807","article-title":"Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1\/2","volume":"68","author":"Lin","year":"2008","journal-title":"Cancer Res."},{"key":"2023012512001202100_B16","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1093\/bib\/bbp025","article-title":"Computational methods for the detection of cis-regulatory modules","volume":"10","author":"Loo","year":"2009","journal-title":"Brief. Bioinform."},{"key":"2023012512001202100_B17","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1111\/j.1440-1681.1998.tb02179.x","article-title":"Multiple comparison procedures updated","volume":"25","author":"Ludbrook","year":"1998","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"2023012512001202100_B18","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.clpt.2006.09.003","article-title":"Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance","volume":"80","author":"Neuvonen","year":"2006","journal-title":"Clin. Pharmacol. Ther."},{"key":"2023012512001202100_B19","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0014-2999(02)01938-6","article-title":"3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors increase the binding activity and nuclear level of oct-1 in mononuclear cells","volume":"448","author":"Ortego","year":"2002","journal-title":"Eur. J. Pharmacol."},{"key":"2023012512001202100_B20","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1002\/jcb.21757","article-title":"Regulation of hmg-coa reductase expression by hypoxia","volume":"104","author":"Pallottini","year":"2008","journal-title":"J. Cell Biochem."},{"key":"2023012512001202100_B21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.pharmtox.47.120505.105349","article-title":"The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences","volume":"48","author":"Pascussi","year":"2008","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"2023012512001202100_B22","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1038\/aps.2009.85","article-title":"The expression of efflux and uptake transporters are regulated by statins in caco-2 and hepg2 cells","volume":"30","author":"Rodrigues","year":"2009","journal-title":"Acta Pharmacol. Sin."},{"key":"2023012512001202100_B23","doi-asserted-by":"crossref","first-page":"e13876","DOI":"10.1371\/journal.pone.0013876","article-title":"Predicting DNA-binding specificities of eukaryotic transcription factors","volume":"5","author":"Schr\u00f6der","year":"2010","journal-title":"PLoS One"},{"key":"2023012512001202100_B24","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1186\/1471-2105-8-334","article-title":"EDISA: extracting biclusters from multiple time-series of gene expression profiles","volume":"8","author":"Supper","year":"2007","journal-title":"BMC Bioinformatics"},{"key":"2023012512001202100_B25","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/1752-0509-3-67","article-title":"BowTieBuilder: modeling signal transduction pathways","volume":"3","author":"Supper","year":"2009","journal-title":"BMC Syst. Biol."},{"key":"2023012512001202100_B26","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1093\/cvr\/cvn007","article-title":"Simvastatin has an anti-inflammatory effect on macrophages via upregulation of an atheroprotective transcription factor, Kruppel-like factor 2","volume":"78","author":"Tuomisto","year":"2008","journal-title":"Cardiovasc Res."},{"key":"2023012512001202100_B27","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.abb.2003.10.009","article-title":"Vitamin E, nuclear receptors and xenobiotic metabolism","volume":"423","author":"Traber","year":"2004","journal-title":"Arch. Biochem. Biophys."},{"key":"2023012512001202100_B28","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.biocel.2009.10.002","article-title":"Hif-1beta determines abca1 expression under hypoxia in human macrophages","volume":"42","author":"Ugocsai","year":"2010","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2023012512001202100_B29","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1159\/000185525","article-title":"Transcriptional regulation of HMG-CoA synthase and HMG-CoA reductase genes by human ACBP","volume":"22","author":"Vock","year":"2008","journal-title":"Cell Physiol. Biochem."},{"key":"2023012512001202100_B30","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/nrg1315","article-title":"Applied bioinformatics for the identification of regulatory elements","volume":"5","author":"Wasserman","year":"2004","journal-title":"Nat. Rev. Genet."},{"key":"2023012512001202100_B31","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1093\/nar\/25.1.265","article-title":"TRANSFAC, TRRD and COMPEL: towards a federated database system on transcriptional regulation","volume":"25","author":"Wingender","year":"1997","journal-title":"Nucleic Acids Res."},{"key":"2023012512001202100_B32","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.biosystems.2009.09.005","article-title":"ModuleMaster: a new tool to decipher transcriptional regulatory networks","volume":"99","author":"Wrzodek","year":"2010","journal-title":"Biosystems"},{"key":"2023012512001202100_B33","doi-asserted-by":"crossref","first-page":"10948","DOI":"10.1074\/jbc.273.18.10948","article-title":"Regulation of peroxisome proliferator-activated receptor alpha-induced transactivation by the nuclear orphan receptor TAK1\/TR4","volume":"273","author":"Yan","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2023012512001202100_B34","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1148\/radiol.2273011499","article-title":"Correlation and simple linear regression","volume":"227","author":"Zou","year":"2003","journal-title":"Radiology"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/27\/18\/2473\/48865251\/bioinformatics_27_18_2473.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/27\/18\/2473\/48865251\/bioinformatics_27_18_2473.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T03:11:51Z","timestamp":1741317111000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/27\/18\/2473\/179914"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,7,14]]},"references-count":34,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2011,9,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btr416","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"type":"electronic","value":"1367-4811"},{"type":"print","value":"1367-4803"}],"subject":[],"published-other":{"date-parts":[[2011,9,15]]},"published":{"date-parts":[[2011,7,14]]}}}