NF-?B-dependent redistribution of the GR cistrome recruits GR to inflammatory gene loci and correlates with reduced repression by glucocorticoid
While ligand-activated glucocorticoid receptor (GR) binds DNA to activate transcription, glucocorticoids, including budesonide, reduce inflammatory gene expression, yet recruit GR to many such gene loci. In epithelial cells, the inflammatory cytokine, interleukin-1ß (IL1B), activates NF-?B to induce gene expression and co-treatment with budesonide produces nanoscale GR-RELA nuclear co-localization. Such co-stimulation orchestrated reciprocal genome-wide redistribution of GR and RELA binding regions (GBRs and RBRs, respectively) relative to each mono-treatment to produce widespread GBR_x0002_RBR overlap. This correlated with increased RNA polymerase-2 presence and required NF-?B for GR cistrome remodeling. Mapping transcription start sites to the nearest GBR or RBR both revealed associations with upregulated, but not repressed, genes. Importantly, RBR proximity to budesonide_x0002_upregulated genes and GBR proximity to IL1B-upregulated genes correlated with attenuated repression on co-treatment. As this occurred on a background of glucocorticoid-induced repression, GR presence at specific IL1B-induced gene loci may reduce, or protect, from an otherwise prevalent glucocorticoid_x0002_induced repression. Overall design: To understand transcriptional interactions between GR and NF-?B, mammalian airway epithelial (A549) cells were not stimulated or treated with IL1B, budesonide, or both for 1, 2, 6, 12, and 24h before harvesting for RNA sequencing.