title: Genetic, functional and molecular features of glucocorticoid receptor binding.
abstract: Glucocorticoids (GCs) are key mediators of stress response and are widely used as pharmacological agents to treat immune diseases, such as asthma and inflammatory bowel disease, and certain types of cancer. GCs act mainly by activating the GC receptor (GR), which interacts with other transcription factors to regulate gene expression. Here, we combined different functional genomics approaches to gain molecular insights into the mechanisms of action of GC. By profiling the transcriptional response to GC over time in 4 Yoruba (YRI) and 4 Tuscans (TSI) lymphoblastoid cell lines (LCLs), we suggest that the transcriptional response to GC is variable not only in time, but also in direction (positive or negative) depending on the presence of specific interacting transcription factors. Accordingly, when we performed ChIP-seq for GR and NF-κB in two YRI LCLs treated with GC or with vehicle control, we observed that features of GR binding sites differ for up- and down-regulated genes. Finally, we show that eQTLs that affect expression patterns only in the presence of GC are 1.9-fold more likely to occur in GR binding sites, compared to eQTLs that affect expression only in its absence. Our results indicate that genetic variation at GR and interacting transcription factors binding sites influences variability in gene expression, and attest to the power of combining different functional genomic approaches.
authors: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.
authors: Francesca
authors: F
authors: Luca
authors: Joseph C
authors: JC
authors: Maranville
authors: Allison L
authors: AL
authors: Richards
authors: David B
authors: DB
authors: Witonsky
authors: Matthew
authors: M
authors: Stephens
authors: Anna
authors: A
authors: Di Rienzo
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D040641:Quantitative Trait Loci / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid
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