Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses by potentiating glucocorticoid receptor activity.
bromodomain containing 9 (BRD9)
inflammation
macrophages
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
31 08 2021
31 08 2021
Historique:
entrez:
27
8
2021
pubmed:
28
8
2021
medline:
21
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34446564
pii: 2109517118
doi: 10.1073/pnas.2109517118
pmc: PMC8536317
pii:
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Brd9 protein, mouse
0
Receptors, Glucocorticoid
0
Transcription Factors
0
Dexamethasone
7S5I7G3JQL
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL088093
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM128943
Pays : United States
Organisme : NIEHS NIH HHS
ID : P42 ES010337
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK120480
Pays : United States
Organisme : NIDDK NIH HHS
ID : R37 DK057978
Pays : United States
Organisme : NIDDK NIH HHS
ID : K01 DK120808
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL105278
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK057978
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014195
Pays : United States
Informations de copyright
Copyright © 2021 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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