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Genome-Wide Discovery of Drug-Dependent Human Liver Regulatory Elements
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نویسنده
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smith r.p. ,eckalbar w.l. ,morrissey k.m. ,luizon m.r. ,hoffmann t.j. ,sun x. ,jones s.l. ,force aldred s. ,ramamoorthy a. ,desta z. ,liu y. ,skaar t.c. ,trinklein n.d. ,giacomini k.m. ,ahituv n.
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منبع
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plos genetics - 2014 - دوره : 10 - شماره : 10
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چکیده
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Inter-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. © 2014 smith et al.
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آدرس
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department of bioengineering and therapeutic sciences,university of california,san francisco,san francisco,ca,united states,institute for human genetics,university of california,san francisco,san francisco,ca, United States, department of bioengineering and therapeutic sciences,university of california,san francisco,san francisco,ca,united states,institute for human genetics,university of california,san francisco,san francisco,ca, United States, department of bioengineering and therapeutic sciences,university of california,san francisco,san francisco,ca, United States, department of bioengineering and therapeutic sciences,university of california,san francisco,san francisco,ca,united states,institute for human genetics,university of california,san francisco,san francisco,ca, United States, institute for human genetics,university of california,san francisco,san francisco,ca,united states,department of epidemiology and biostatistics,university of california,san francisco,san francisco,ca, United States, department of bioengineering and therapeutic sciences,university of california,san francisco,san francisco,ca,united states,institute for human genetics,university of california,san francisco,san francisco,ca, United States, department of bioengineering and therapeutic sciences,university of california,san francisco,san francisco,ca,united states,institute for human genetics,university of california,san francisco,san francisco,ca, United States, switchgear genomics,menlo park,ca, United States, department of medicine,division of clinical pharmacology,indiana university school of medicine,indianapolis,in,united states,department of medical and molecular genetics,indiana university school of medicine,indianapolis,in, United States, department of medicine,division of clinical pharmacology,indiana university school of medicine,indianapolis,in, United States, department of medical and molecular genetics,indiana university school of medicine,indianapolis,in, United States, department of medicine,division of clinical pharmacology,indiana university school of medicine,indianapolis,in, United States, switchgear genomics,menlo park,ca, United States, department of bioengineering and therapeutic sciences,university of california,san francisco,san francisco,ca,united states,institute for human genetics,university of california,san francisco,san francisco,ca, United States, department of bioengineering and therapeutic sciences,university of california,san francisco,san francisco,ca,united states,institute for human genetics,university of california,san francisco,san francisco,ca, United States
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Authors
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