Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses by potentiating glucocorticoid receptor activity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 35; pp. 1 - 9
• Main Authors: Wang, Liu, Oh, Tae Gyu, Magida, Jason, Estepa, Gabriela, Obayomi, S. M. Bukola, Chong, Ling-Wa, Gatchalian, Jovylyn, Yu, Ruth T., Atkins, Annette R., Hargreaves, Diana, Downes, Michael, Wei, Zong, Evans, Ronald M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 31-08-2021
• Subjects: Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - pharmacology; Biological Sciences; Bone marrow; Chromatin Assembly and Disassembly; Chromatin remodeling; Dexamethasone; Dexamethasone - pharmacology; Gene expression; Gene Expression Regulation; Glucocorticoids; Inflammation; Inflammatory response; Interferon; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Protein Domains; Receptors; Receptors, Glucocorticoid - antagonists & inhibitors; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; inflammation; bromodomain containing 9 (BRD9); macrophages
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2109517118

In macrophages, homeostatic and immune signals induce distinct sets of transcriptional responses, defining cellular identity and functional states. The activity of lineage-specific and signal-induced transcription factors are regulated by chromatin accessibility and other epigenetic modulators. Glucocorticoids are potent antiinflammatory drugs; however, the mechanisms by which they selectively attenuate inflammatory genes are not yet understood. Acting through the glucocorticoid receptor (GR), glucocorticoids directly repress inflammatory responses at transcriptional and epigenetic levels in macrophages. A major unanswered question relates to the sequence of events that result in the formation of repressive regions. In this study, we identify bromodomain containing 9 (BRD9), a component of SWI/SNF chromatin remodeling complex, as a modulator of glucocorticoid responses in macrophages. Inhibition, degradation, or genetic depletion of BRD9 in bone marrow-derived macrophages significantly attenuated their responses to both liposaccharides and interferon inflammatory stimuli. Notably, BRD9-regulated genes extensively overlap with those regulated by the synthetic glucocorticoid dexamethasone. Pharmacologic inhibition of BRD9 potentiated the antiinflammatory responses of dexamethasone, while the genetic deletion of BRD9 in macrophages reduced high-fat diet-induced adipose inflammation. Mechanistically, BRD9 colocalized 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.