title: Discovery of Transcriptional Targets Regulated by Nuclear Receptors Using a Probabilistic Graphical Model.
abstract: Nuclear receptors (NRs) are ligand-activated transcriptional regulators that play vital roles in key biological processes such as growth, differentiation, metabolism, reproduction, and morphogenesis. Disruption of NRs can result in adverse health effects such as NR-mediated endocrine disruption. A comprehensive understanding of core transcriptional targets regulated by NRs helps to elucidate their key biological processes in both toxicological and therapeutic aspects. In this study, we applied a probabilistic graphical model to identify the transcriptional targets of NRs and the biological processes they govern. The Tox21 program profiled a collection of approximate 10 000 environmental chemicals and drugs against a panel of human NRs in a quantitative high-throughput screening format for their NR disruption potential. The Japanese Toxicogenomics Project, one of the most comprehensive efforts in the field of toxicogenomics, generated large-scale gene expression profiles on the effect of 131 compounds (in its first phase of study) at various doses, and different durations, and their combinations. We applied author-topic model to these 2 toxicological datasets, which consists of 11 NRs run in either agonist and/or antagonist mode (18 assays total) and 203 in vitro human gene expression profiles connected by 52 shared drugs. As a result, a set of clusters (topics), which consists of a set of NRs and their associated target genes were determined. Various transcriptional targets of the NRs were identified by assays run in either agonist or antagonist mode. Our results were validated by functional analysis and compared with TRANSFAC data. In summary, our approach resulted in effective identification of associated/affected NRs and their target genes, providing biologically meaningful hypothesis embedded in their relationships.
authors.affiliation: *NIH/National Center for Advancing Translational Sciences, Rockville, Maryland 20850 and.
authors.forename: Mikyung
authors.initials: M
authors.lastname: Lee
authors.affiliation: *NIH/National Center for Advancing Translational Sciences, Rockville, Maryland 20850 and.
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.affiliation: FDA/National Center for Toxicological Research, Jefferson, Arkansas 72079 Weida.tong@fda.hhs.gov.
authors.forename: Weida
authors.initials: W
authors.lastname: Tong
mesh_terms: D003196:Computer Graphics; D066264:Datasets as Topic; D052244:Endocrine Disruptors / Q000633:toxicity; D020869:Gene Expression Profiling; D006801:Humans; D015233:Models, Statistical; D008962:Models, Theoretical; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D043922:Toxicogenetics / Q000379:methods* / Q000706:statistics & numerical data; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D052244:Endocrine Disruptors; D018160:Receptors, Cytoplasmic and Nuclear
keywords: Tox21; author-topic model; integrative analysis; nuclear receptor; toxicogenomics project; transcriptional regulation