Insights into Negative Regulation by the Glucocorticoid Receptor from Genome-wide Profiling of Inflammatory Cistromes

SummaryHow 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.

Graphical AbstractFigure optionsDownload high-quality image (136 K)Download as PowerPoint slideHighlights
► TLR4 activation dramatically remodels the GR cistrome in macrophages
► Both negative and positive GR enhancers include GREs, NF-κB, and AP-1 sites
► Classical models fail to predict positive or negative polarity of GR regulation
► Hormone treatment marks negative enhancers by histone deacetylation