Research resource: Tissue-specific transcriptomics and cistromics of nuclear receptor signaling: a web research resource

Abstract

Nuclear receptors (NRs) are ligand-regulated transcription factors that recruit coregulators and other transcription factors to gene promoters to effect regulation of tissue-specific transcriptomes. The prodigious rate at which the NR signaling field has generated high content gene expression and, more recently, genome-wide location analysis datasets has not been matched by a committed effort to archiving this information for routine access by bench and clinical scientists. As a first step towards this goal, we searched the MEDLINE database for studies, which referenced either expression microarray and/or genome-wide location analysis datasets in which a NR or NR ligand was an experimental variable. A total of 1122 studies encompassing 325 unique organs, tissues, primary cells, and cell lines, 35 NRs, and 91 NR ligands were retrieved and annotated. The data were incorporated into a new section of the Nuclear Receptor Signaling Atlas Molecule Pages, Transcriptomics and Cistromics, for which we designed an intuitive, freely accessible user interface to browse the studies. Each study links to an abstract, the MEDLINE record, and, where available, Gene Expression Omnibus and ArrayExpress records. The resource will be updated on a regular basis to provide a current and comprehensive entrez into the sum of transcriptomic and cistromic research in this field.

Figure 1

Nuclear receptor ligands used to generate expression microarray datasets described in this study. The Physiological category includes endogenously synthesized bioactive ligands, their precursors and metabolites. The Clinical category includes approved therapeutic ligands. EDCs are compounds that have therapeutic or industrial uses but which in the context of nuclear receptor signaling are classified as disrupting chemicals. The Experimental category includes ligands used in basic research as well as therapeutic candidates not yet approved for use in the clinic. Dietary ligands include those ingested as part of the diet. For receptor subfamilies, ligands are pan-agonists unless otherwise indicated by superscript symbols representing the specific isoforms. 15PJG2, 15-Deoxy-δ-12,14-prostaglandin J2; 5α-diol, 5α-androstane 3α,17β-diol; CDCA, chenodeoxycholic acid; DDT, 1-chloro-4-[2,2,2-trichloro-1-(4-chlorophenyl)ethyl]benzene; DHEA, dihydroepiandrosterone; DOCO, docosahexanoic acid; EICO, eicosapentaenoic acid; PCN, pregnenolone carbonitrile. Only ligands currently curated by NURSA were included in the Figure. Datasets for all ligands have been compiled and annotated and are accessible in the Transcriptomics and Cistromics section of the individual Ligand Pages on the NURSA website at www.nursa.org.

Figure 2

Distinct NR signaling pathways direct tissue-specific programs of gene expression. Data were generated as described in the text. For raw data, please see Supplemental data. Note that due to space constraints, some ligand-receptor groups referred to in Figure 1 are omitted from this figure. These include those for which studies were present in too few numbers (MR and LXR ligands) or which were carried out almost exclusively in a single tissue (PXR, FXR, and CAR ligands in the liver). These studies have, however, been annotated and can be found, along with all the other studies, in the Transcriptomics and Cistromics section of the appropriate Receptor and Ligand Pages on the NURSA website. GI, Gastrointestinal; CNS, central nervous system.

Figure 3

A, Orphan NRs are key regulators of gene expression in metabolic organs. Tissues with critical roles in the regulation of energy metabolism [liver, central nervous system, cardiovascular, fat, pancreas, gastrointestinal (GI) tract, and other metabolic tissues, such as kidney, adrenal gland, and bone] constitute nearly 75% of orphan NR-based expression array datasets. Data were compiled from 47 expression array and GWLA datasets in which the function of an orphan NR was experimentally perturbed. Receptors studied were DAX1, SHP, RORα, RORγ, HNF4α, COUPTF-I, ERRα, ERRβ, ERRγ, NUR77, NURR1, and SF-1. Raw data are available in Supplemental data. Datasets for all orphan NRs have been compiled and annotated and are accessible in the Transcriptomics and Cistromics section of the individual Receptor Pages on the NURSA website. B, EDCs are transcriptionally active in female and male reproductive tissues. For details, please see text. Datasets for all EDCs have been compiled and annotated and are accessible in the Transcriptomics and Cistromics section of the individual Receptor and Ligand Pages on the NURSA website. CNS, Central nervous system.