Schröder, Adrian and Wollnik, Johannes and Wrzodek, Clemens and Dräger, Andreas and Bonin, Michael and Burk, Oliver and Thomas, Maria and Thasler, Wolfgang E. and Zanger, Ulrich M. and Zell, Andreas

Inferring statin-induced gene regulatory relationships in primary human hepatocytes

Bioinformatics vol. 27 (2011), no. 18, pp. 2473-2477


Abstract

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 TF binding specificities, and protein-drug interactions. Several previously unknown transcription factors 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 http://www.ncbi.nlm.nih.gov/geo/, under accession number GSE29868.


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BibTeX

@article{Schroeder2011b,
  author = {Schr\"oder, Adrian and Wollnik, Johannes and Wrzodek, Clemens and
	Dr\"ager, Andreas and Bonin, Michael and Burk, Oliver and Thomas,
	Maria and Thasler, Wolfgang E. and Zanger, Ulrich M. and Zell, Andreas},
  title = {Inferring statin-induced gene regulatory relationships in primary
	human hepatocytes},
  journal = {Bioinformatics},
  year = {2011},
  volume = {27},
  pages = {2473--2477},
  number = {18},
  month = jul,
  abstract = {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 TF binding specificities, and
	protein-drug interactions. Several previously unknown transcription
	factors 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 \url{http://www.ncbi.nlm.nih.gov/geo/},
	under accession number GSE29868.},
  doi = {10.1093/bioinformatics/btr416},
  pdf = {http://bioinformatics.oxfordjournals.org/content/27/18/2473.full.pdf},
  url = {http://bioinformatics.oxfordjournals.org/content/27/18/2473.abstract}
}