The GR at inflammatory crossroads

The Glucocorticoid Receptor (GR) is one of the most potent anti-inflammatory drug targets in clinical use today and one of the most powerful metabolic regulators. It is believed that the anti-inflammatory actions of glucocorticoids are predominantly based on gene repression whereas many unwanted side-effects of steroid treatment (such as hyperglycemia and obesity) are due to transcriptional activation. Yet how the GR activates some genes while potently repressing others, remains an unresolved molecular paradox. Current models for suppression favor either trans-repression, with GR 'tethering' to AP-1/NF-κB, association with inhibitory nGREs, or recruitment of the corepressor GRIP1. Using genomic analyses in LPS-stimulated macrophages, we show that upon TLR4 activation, the GR cistrome features classical GREs together with NF-κB and AP-1 motifs at both up- and down-regulated genes, excluding the concept that these factors oppose each other. Surprisingly, tethered sites, GREs and GRIP1 support positive as well as negative regulation. Classical models hence fail to predict the polarity of GR regulation. Interestingly, negative enhancers appear to be correlated with IRF3 occupancy. These sites utilize GRIP1's corepressor function and are characterized by reduced histone acetylation patterns. This implies that transcriptional outcome is established by epigenetic regulators and context rather than sequence and suggests the existence of unrecognized regulatory determinants.