Multi-omics analysis of glucocorticoid receptor crosstalk with Type I and Type II inflammatory signaling in human airway smooth muscle cells.

Airway smooth muscle (ASM) dysfunction in obstructive airway disease is treated with glucocorticoids. Through RNA-seq analysis of cultured human ASM, we identified repressive effects of dexamethasone, a glucocorticoid, on the baseline expression of a subset of genes that are induced by either IL1B or IL13, which model Type I and Type II inflammation, respectively. ChIP-seq analysis of glucocorticoid receptor (GR) and the p65 subunit of NFkB occupancy indicated canonical motifs for both factors occur at sites of p65 occupancy but did not provide biochemical support for significant repressive tethering between GR and p65. Instead, ATAC-seq revealed significant chromatin remodeling and increased accessibility at binding motifs for the NFkB complex in association with dex + IL1B co-treatment in comparison to IL1B treatment alone. Our data support a competition-based primary repressive effect of glucocorticoids on both IL1B and IL13 signaling and provide evidence for transcriptional cooperation between GR and NFkB on a genome-wide basis in ASM, including at regulatory elements that control expression of anti-inflammatorygenes.