# NF-κB-dependent GR cistrome redistribution recruits GR to inflammatory genes but correlates with lesser glucocorticoid-mediated repression

## TL;DR

This study shows that glucocorticoids like budesonide can recruit the glucocorticoid receptor (GR) to inflammatory genes, but this recruitment is linked to reduced repression of those genes.

## Contribution

The paper reveals that GR cistrome redistribution, driven by NF-κB, correlates with less repression of inflammatory genes during co-treatment with IL1B and budesonide.

## Key findings

- GR and RELA co-localization correlates with RNA polymerase-2 presence and gene upregulation.
- GR cistrome redistribution is dependent on NF-κB activation.
- Inflammatory genes that recruit GR show reduced repression by budesonide.

## Abstract

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-1β (IL1B), activates nuclear factor (NF)-κB 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-RBR overlap. This correlated with increased RNA polymerase-2 presence and required NF-κB for GR cistrome remodeling. Mapping transcription start sites to the nearest GBR or RBR each revealed associations with upregulated, but not repressed, genes. Importantly, RBR proximity to budesonide-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/protect from an otherwise more prevalent glucocorticoid-induced repression.

•GR and RELA recruitment correlate with RNA polymerase-2 and gene upregulation•IL1B-plus-budesonide redistributes each cistrome to produce mutual GR/RELA overlap•GR cistrome redistribution is NF-κB dependent•Inflammatory genes that recruit GR reveal less repression by budesonide

GR and RELA recruitment correlate with RNA polymerase-2 and gene upregulation

IL1B-plus-budesonide redistributes each cistrome to produce mutual GR/RELA overlap

GR cistrome redistribution is NF-κB dependent

Inflammatory genes that recruit GR reveal less repression by budesonide

Genomics; Gene network; Molecular mechanism of gene regulation