Genome-Wide Discovery of Drug-Dependent Human Liver Regulatory Elements

dc.contributor.authorSmith, Robin P.
dc.contributor.authorEckalbar, Walter L.
dc.contributor.authorMorrissey, Kari M.
dc.contributor.authorLuizon, Marcelo R.
dc.contributor.authorHoffmann, Thomas J.
dc.contributor.authorSun, Xuefeng
dc.contributor.authorJones, Stacy L.
dc.contributor.authorAldred, Shelley Force
dc.contributor.authorRamamoorthy, Anuradha
dc.contributor.authorDesta, Zeruesenay
dc.contributor.authorLiu, Yunlong
dc.contributor.authorSkaar, Todd C.
dc.contributor.authorTrinklein, Nathan D.
dc.contributor.authorGiacomini, Kathleen M.
dc.contributor.authorAhituv, Nadav
dc.contributor.departmentDepartment of Medicine, School of Medicineen_US
dc.date.accessioned2015-09-28T16:37:35Z
dc.date.available2015-09-28T16:37:35Z
dc.date.issued2014-10-02
dc.description.abstractInter-individual variation in gene regulatory elements is hypothesized to play a causative role in adverse drug reactions and reduced drug activity. However, relatively little is known about the location and function of drug-dependent elements. To uncover drug-associated elements in a genome-wide manner, we performed RNA-seq and ChIP-seq using antibodies against the pregnane X receptor (PXR) and three active regulatory marks (p300, H3K4me1, H3K27ac) on primary human hepatocytes treated with rifampin or vehicle control. Rifampin and PXR were chosen since they are part of the CYP3A4 pathway, which is known to account for the metabolism of more than 50% of all prescribed drugs. We selected 227 proximal promoters for genes with rifampin-dependent expression or nearby PXR/p300 occupancy sites and assayed their ability to induce luciferase in rifampin-treated HepG2 cells, finding only 10 (4.4%) that exhibited drug-dependent activity. As this result suggested a role for distal enhancer modules, we searched more broadly to identify 1,297 genomic regions bearing a conditional PXR occupancy as well as all three active regulatory marks. These regions are enriched near genes that function in the metabolism of xenobiotics, specifically members of the cytochrome P450 family. We performed enhancer assays in rifampin-treated HepG2 cells for 42 of these sequences as well as 7 sequences that overlap linkage-disequilibrium blocks defined by lead SNPs from pharmacogenomic GWAS studies, revealing 15/42 and 4/7 to be functional enhancers, respectively. A common African haplotype in one of these enhancers in the GSTA locus was found to exhibit potential rifampin hypersensitivity. Combined, our results further suggest that enhancers are the predominant targets of rifampin-induced PXR activation, provide a genome-wide catalog of PXR targets and serve as a model for the identification of drug-responsive regulatory elements.en_US
dc.identifier.citationSmith, R. P., Eckalbar, W. L., Morrissey, K. M., Luizon, M. R., Hoffmann, T. J., Sun, X., … Ahituv, N. (2014). Genome-Wide Discovery of Drug-Dependent Human Liver Regulatory Elements. PLoS Genetics, 10(10), e1004648. http://doi.org/10.1371/journal.pgen.1004648en_US
dc.identifier.urihttps://hdl.handle.net/1805/7061
dc.language.isoen_USen_US
dc.publisherPLOS (Public Library of Science)en_US
dc.relation.isversionof10.1371/journal.pgen.1004648en_US
dc.relation.journalPLoS Geneticsen_US
dc.rightsAttribution 3.0 United States
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/
dc.sourcePMCen_US
dc.subjectHepatocytesen_US
dc.subjectGene expressionen_US
dc.subjectHaplotypesen_US
dc.subjectDrug metabolismen_US
dc.subjectGenome-wide association studiesen_US
dc.subjectDrug therapyen_US
dc.subjectEnzyme metabolismen_US
dc.subjectGene regulationen_US
dc.titleGenome-Wide Discovery of Drug-Dependent Human Liver Regulatory Elementsen_US
dc.typeArticleen_US
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