title: Research Resource: A Reference Transcriptome for Constitutive Androstane Receptor and Pregnane X Receptor Xenobiotic Signaling.
abstract: The pregnane X receptor (PXR) (PXR/NR1I3) and constitutive androstane receptor (CAR) (CAR/NR1I2) members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors are well-characterized mediators of xenobiotic and endocrine-disrupting chemical signaling. The Nuclear Receptor Signaling Atlas maintains a growing library of transcriptomic datasets involving perturbations of NR signaling pathways, many of which involve perturbations relevant to PXR and CAR xenobiotic signaling. Here, we generated a reference transcriptome based on the frequency of differential expression of genes across 159 experiments compiled from 22 datasets involving perturbations of CAR and PXR signaling pathways. In addition to the anticipated overrepresentation in the reference transcriptome of genes encoding components of the xenobiotic stress response, the ranking of genes involved in carbohydrate metabolism and gonadotropin action sheds mechanistic light on the suspected role of xenobiotics in metabolic syndrome and reproductive disorders. Gene Set Enrichment Analysis showed that although acetaminophen, chlorpromazine, and phenobarbital impacted many similar gene sets, differences in direction of regulation were evident in a variety of processes. Strikingly, gene sets representing genes linked to Parkinson's, Huntington's, and Alzheimer's diseases were enriched in all 3 transcriptomes. The reference xenobiotic transcriptome will be supplemented with additional future datasets to provide the community with a continually updated reference transcriptomic dataset for CAR- and PXR-mediated xenobiotic signaling. Our study demonstrates how aggregating and annotating transcriptomic datasets, and making them available for routine data mining, facilitates research into the mechanisms by which xenobiotics and endocrine-disrupting chemicals subvert conventional NR signaling modalities.
authors.affiliation: Departments of Molecular and Cellular Biology (S.A.O., J.D., C.C., N.J.M.) and Lester and Sue Smith Breast Center (A.T.) and the Nuclear Receptor Signaling Atlas Informatics Group (S.A.O., N.J.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Ochsner
authors.affiliation: Departments of Molecular and Cellular Biology (S.A.O., J.D., C.C., N.J.M.) and Lester and Sue Smith Breast Center (A.T.) and the Nuclear Receptor Signaling Atlas Informatics Group (S.A.O., N.J.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.affiliation: Departments of Molecular and Cellular Biology (S.A.O., J.D., C.C., N.J.M.) and Lester and Sue Smith Breast Center (A.T.) and the Nuclear Receptor Signaling Atlas Informatics Group (S.A.O., N.J.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Dong
authors.affiliation: Departments of Molecular and Cellular Biology (S.A.O., J.D., C.C., N.J.M.) and Lester and Sue Smith Breast Center (A.T.) and the Nuclear Receptor Signaling Atlas Informatics Group (S.A.O., N.J.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Departments of Molecular and Cellular Biology (S.A.O., J.D., C.C., N.J.M.) and Lester and Sue Smith Breast Center (A.T.) and the Nuclear Receptor Signaling Atlas Informatics Group (S.A.O., N.J.M.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: McKenna
mesh_terms: D000818:Animals; D000090702:Constitutive Androstane Receptor; D057225:Data Mining; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011987:Receptors, Steroid / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*; D015262:Xenobiotics / Q000494:pharmacology
chemical_list: D000090702:Constitutive Androstane Receptor; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D015262:Xenobiotics