title: Insights into negative regulation by the glucocorticoid receptor from genome-wide profiling of inflammatory cistromes.
abstract: How the glucocorticoid receptor (GR) activates some genes while potently repressing others remains an open question. There are three current models for suppression: transrepression via GR tethering to AP-1/NF-κB sites, direct GR association with inhibitory elements (nGREs), and GR recruitment of the corepressor GRIP1. To gain insights into GR suppression, we used genomic analyses and genome-wide profiling of GR, p65, and c-Jun in LPS-stimulated macrophages. We show that GR mediates both activation and repression at tethered sites, GREs, and GRIP1-bound elements, indicating that motif classification is insufficient to predict regulatory polarity of GR binding. Interestingly, sites of GR repression utilize GRIP1's corepressor function and display reduced histone acetylation. Together, these findings suggest that while GR occupancy confers hormone responsiveness, the receptor itself may not participate in the regulatory effects. Furthermore, transcriptional outcome is not established by sequence but is influenced by epigenetic regulators, context, and other unrecognized regulatory determinants.
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: N Henriette
authors.initials: NH
authors.lastname: Uhlenhaut
authors.forename: Grant D
authors.initials: GD
authors.lastname: Barish
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.forename: Malith
authors.initials: M
authors.lastname: Karunasiri
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.forename: Petra
authors.initials: P
authors.lastname: Schwalie
authors.forename: Norbert
authors.initials: N
authors.lastname: Hübner
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D002874:Chromosome Mapping; D016000:Cluster Analysis; D016384:Consensus Sequence; D003907:Dexamethasone / Q000494:pharmacology; D044127:Epigenesis, Genetic; D016678:Genome; D005938:Glucocorticoids / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005938:Glucocorticoids; C491309:Grip1 protein, mouse; D006657:Histones; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D003907:Dexamethasone