PRJNA731887
Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses by potentiating glucocorticoids receptor activity
In this study, we identify bromodomain containing 9 (BRD9), a component of SWI/SNF chromatin remodeling complex, as a novel modulator of glucocorticoid responses in macrophages. Inhibition, degradation, or genetic depletion of BRD9 in bone marrow derived macrophages (BMDMs) significantly attenuated their responses to both liposaccharides (LPS) and interferon inflammatory stimuli. Notably, BRD9-regulated genes extensively overlap with those regulated by the synthetic glucocorticoid dexamethasone. Pharmacologic inhibition of BRD9 potentiated the anti-inflammatory responses of dexamethasone, while the genetic deletion of BRD9 in macrophages reduced high fat diet induced adipose inflammation. Mechanistically, BRD9 co-localized at a subset of GR genomic binding sites, and depletion of BRD9 enhanced GR occupancy primarily at inflammatory-related genes to potentiate GR-induced repression. Collectively, these findings establish BRD9 as a genomic antagonist of GR at inflammatory-related genes in macrophages, and reveal a potential for BRD9 inhibitors to increase the therapeutic efficacies of glucocorticoids.