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Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses and modulates glucocorticoids receptor activity.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE175585 | GEO | 2021/08/23

REPOSITORIES: GEO

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Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses and modulates glucocorticoids receptor activity [CUT&RUN]

Project description:In macrophages, homeostatic and immune signals induce distinct sets of transcriptional responses, defining the cellular identity and function. The activity of lineage specific and signal induced transcription factors are regulated by chromatin accessibility and other epigenetic modulators. Glucocorticoids are potent anti-inflammatory drugs. Acting through the glucocorticoid receptor (GR), glucocorticoids directly repress inflammatory responses at transcriptional and epigenetic levels in macrophages. In this study, we identified bromodomain containing 9 (BRD9), a component of SWI/SNF chromatin remodeling complex, as a novel modulator for glucocorticoids responses in macrophages. Inhibition, degradation, or genetic depletion of BRD9 in bone marrow derived macrophages (BMDM), significantly compromised their responses to inflammatory stimuli, such as liposaccharides (LPS), and interferons. A large portion of BRD9-regulated genes are also known to be regulated by dexamethasone, a synthetic glucocorticoid. Importantly, pharmacologic inhibition of BRD9 is able to further potentiate the anti-inflammatory responses of dexamethasone, by further repressing the GR downstream targets. Mechanistically, BRD9 co-localized with a subset of GR binding sites. Depletion of BRD9 enhanced GR occupancy at a subset of its targets. Enhanced occupancy of GR at these sites is associated with further repression of inflammation-related genes. Collectively, these findings establish BRD9 as a key modulator of macrophage inflammatory responses, revealing the therapeutic potential of BRD9 inhibitors as modulators for glucocorticoids action.

2021-08-23 | GSE175583 | GEO

Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses and modulates glucocorticoids receptor activity [ChIP-seq]

2021-08-23 | GSE175582 | GEO

Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses and modulates glucocorticoids receptor activity [RNA-seq]

2021-08-23 | GSE175584 | GEO

Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses and modulates glucocorticoids receptor activity.

Project description:Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses and modulates glucocorticoids receptor activity.

| PRJNA732934 | ENA

Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses and modulates glucocorticoids receptor activity [CUT&RUN]

Project description:Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses and modulates glucocorticoids receptor activity [CUT&RUN]

| PRJNA732939 | ENA

Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses and modulates glucocorticoids receptor activity [RNA-seq]

Project description:Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses and modulates glucocorticoids receptor activity [RNA-seq]

| PRJNA732940 | ENA

Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses and modulates glucocorticoids receptor activity [ChIP-seq]

Project description:Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses and modulates glucocorticoids receptor activity [ChIP-seq]

| PRJNA732938 | ENA

Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition.

Project description:Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain "reader" modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.

| S-EPMC7354103 | biostudies-literature

BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses.

Project description:BRD4 is a BET family protein that binds acetylated histones and regulates transcription. BET/BRD4 inhibitors block blood cancer growth and inflammation and serve as a new therapeutic strategy. However, the biological role of BRD4 in normal hematopoiesis and inflammation is not fully understood. Analysis of Brd4 conditional knockout (KO) mice showed that BRD4 is required for hematopoietic stem cell expansion and progenitor development. Nevertheless, BRD4 played limited roles in macrophage development and inflammatory response to LPS ChIP-seq analysis showed that despite its limited importance, BRD4 broadly occupied the macrophage genome and participated in super-enhancer (SE) formation. Although BRD4 is critical for SE formation in cancer, BRD4 was not required for macrophage SEs, as KO macrophages created alternate, BRD4-less SEs that compensated BRD4 loss. This and additional mechanisms led to the retention of inflammatory responses in macrophages. Our results illustrate a context-dependent role of BRD4 and plasticity of epigenetic regulation.

| S-EPMC6443207 | biostudies-literature

PIK3CA Cooperates with KRAS to Promote MYC Activity and Tumorigenesis via the Bromodomain Protein BRD9.

Project description:Tumor formation is generally linked to the acquisition of two or more driver genes that cause normal cells to progress from proliferation to abnormal expansion and malignancy. In order to understand genetic alterations involved in this process, we compared the transcriptomes of an isogenic set of breast epithelial cell lines that are non-transformed or contain a single or double knock-in (DKI) of PIK3CA (H1047R) or KRAS (G12V). Gene set enrichment analysis revealed that DKI cells were enriched over single mutant cells for genes that characterize a MYC target gene signature. This gene signature was mediated in part by the bromodomain-containing protein 9 (BRD9) that was found in the SWI-SNF chromatin-remodeling complex, bound to the MYC super-enhancer locus. Small molecule inhibition of BRD9 reduced MYC transcript levels. Critically, only DKI cells had the capacity for anchorage-independent growth in semi-solid medium, and CRISPR-Cas9 manipulations showed that PIK3CA and BRD9 expression were essential for this phenotype. In contrast, KRAS was necessary for DKI cell migration, and BRD9 overexpression induced the growth of KRAS single mutant cells in semi-solid medium. These results provide new insight into the earliest transforming events driven by oncoprotein cooperation and suggest BRD9 is an important mediator of mutant PIK3CA/KRAS-driven oncogenic transformation.

| S-EPMC6896067 | biostudies-literature

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