气候变化领域集成服务门户(CCPortal): Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses by potentiating glucocorticoid receptor activity

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DOI	10.1073/pnas.2109517118
	Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses by potentiating glucocorticoid receptor activity
	Wang L.; Oh T.G.; Magida J.; Estepa G.; Obayomi S.M.B.; Chong L.-W.; Gatchalian J.; Yu R.T.; Atkins A.R.; Hargreaves D.; Downes M.; Wei Z.; Evans R.M.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:35
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Bromodomain containing 9 (BRD9); Inflammation; Macrophages
语种	英语
scopus关键词	antiinflammatory agent; Brd9 protein, mouse; dexamethasone; glucocorticoid receptor; transcription factor; animal; C57BL mouse; chromatin assembly and disassembly; drug effect; gene expression regulation; genetics; immunology; macrophage; male; metabolism; mouse; protein domain; Animals; Anti-Inflammatory Agents; Chromatin Assembly and Disassembly; Dexamethasone; Gene Expression Regulation; Macrophages; Male; Mice; Mice, Inbred C57BL; Protein Domains; Receptors, Glucocorticoid; Transcription Factors
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251033
作者单位	Department of Physiology and Biomedical Engineering, Mayo Clinic Arizona, Scottsdale, AZ 85259, United States; Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, CA 92037, United States; Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, San Diego, CA 92037, United States
推荐引用方式 GB/T 7714	Wang L.,Oh T.G.,Magida J.,et al. Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses by potentiating glucocorticoid receptor activity[J],2021,118(35).
APA	Wang L..,Oh T.G..,Magida J..,Estepa G..,Obayomi S.M.B..,...&Evans R.M..(2021).Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses by potentiating glucocorticoid receptor activity.Proceedings of the National Academy of Sciences of the United States of America,118(35).
MLA	Wang L.,et al."Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses by potentiating glucocorticoid receptor activity".Proceedings of the National Academy of Sciences of the United States of America 118.35(2021).