Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Bromodomain and extra-terminal (BET) inhibitors regulate NK cell biology by inhibiting BRD2 mediated NK cytolytic activity and BRD2/BRD4 mediated inflammatory function

ABSTRACT: Natural killer cells are innate lymphocytes that play a pivotal role in the immune surveillance and elimination of transformed or virally infected cells. Using a combined chemico-genetic approach, we have identified that BET bromodomains BRD2 and BRD4 are central regulators of NK cell responses. We show that both BRD2 and BRD4 play a key regulatory function in controlling NK cell specific inflammatory responses. However, knockdown of BRD2 but not BRD4 impairs NK cell cytolytic response, highlighting a redundant role for BRD4 in regulating NK cell killing. We further show that the prototypic monovalent BET inhibitor impairs in vitro NK cell mediated killing of cancer target cells, while the bivalent BET bromodomain AZD5153 does not. We ascribe these differences to the preferential affinity of JQ1(+) to BRD2, while AZD5153 has a higher affinity for BRD4. Our work suggests that inhibiting BET bromodomains may be an effective therapeutic strategy for controlling inflammatory function. Given that BRD2 but not BRD4 inhibition can impair NK cell mediated killing, our findings also have clinical significance in light of the ongoing clinical application of BET bromodomains in oncology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156423 | GEO | 2021/03/16

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Transcriptome analysis upon Nipbl, Brd2 and Brd4 knockdown in P19 cells

Project description:Mutations in NIPBL are the major cause of Cornelia de Lange Syndrome (CdLS). NIPBL is the cohesin loading factor and has recently been associated with the BET (Bromodomains and Extra Terminal (ET) domain) proteins BRD2 and BRD4. Related to this, a CdLS-like phenotype has been described associated to BRD4 mutations. To understand the relationship between NIPBL and BET proteins, we have performed RNA-Seq expression analysis following depletion of the different proteins in mouse P19 teratocarcinoma cells. Results indicate that genes regulated by NIPBL largely overlap with those regulated by BRD4 but not with those regulated by BRD2.

2020-01-01 | GSE132785 | GEO

Bromodomain and extra-terminal (BET) inhibitors regulate NK cell biology by inhibiting BRD2 mediated NK cytolytic activity and BRD2/BRD4 mediated inflammatory function

Project description:Bromodomain and extra-terminal (BET) inhibitors regulate NK cell biology by inhibiting BRD2 mediated NK cytolytic activity and BRD2/BRD4 mediated inflammatory function

| PRJNA657865 | ENA

Blockade of oncogenic IkappaB kinase activity in ABC DLBCL by small molecule BET protein inhibitors

Project description:In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), NF-kappaB activity is essential for viability of the malignant cells and is sustained by constitutive activity of IkappaB kinase (IKK) in the cytoplasm. Here, we report an unexpected role for the bromodomain and extraterminal domain (BET) proteins BRD2 and BRD4 in maintaining oncogenic IKK activity in ABC DLBCL. IKK activity was reduced by small molecules targeting BET proteins as well as by genetic knockdown of BRD2 and BRD4 expression, thereby inhibiting downstream NF-kappaB-driven transcriptional programs and killing ABC DLBCL cells. Using a high-throughput platform to screen for drug-drug synergy, we observed that the BET inhibitor JQ1 combined favorably with multiple drugs targeting B cell receptor signaling, one pathway that activates IKK in ABC DLBCL. The BTK kinase inhibitor ibrutinib, which is in clinical development for the treatment of ABC DLBCL, synergized strongly with BET inhibitors in killing ABC DLBCL cells in vitro and in a xenograft mouse model. These findings provide a mechanistic basis for the clinical development of BET protein inhibitors in ABC DLBCL, particularly in combination with other modulators of oncogenic IKK signaling. For JQ1 time course gene expression profiling, HBL1 and LP1 cells were treated with either DMSO or 100nM JQ1 for 1h, 3h, 8h, and 24h. For shRNA gene expression profiling, HBL1 cells were infected with either a Ctrl shRNA or with shRNA targeting BRD2 or BRD4. Following puromycin selection, shRNA expression was induced for 1 day and 2 days.

2014-08-01 | E-GEOD-58791 | biostudies-arrayexpress

ChIP-Seq of H4K5acK8ac, H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K9me3, H3K27me3 and BRD2 in H23 NSCLC cell line

Project description:The bromodomain and extra-terminal domain (BET) proteins are known as drug targets in diseases. However, the BET protein association profile to histone H4 hyperacetylation is not well understood and BET inhibition effects have been studied more in the context of BRD4 than BRD2. Here, by integrating chromatin and transcriptome analyses of ChIP-seq and Cap Analysis Gene Expression (CAGE) datasets, we show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Interestingly, although BET inhibition by JQ1 led to complete reduction of BRD2 binding, only local changes of H4K5acK8ac were observed and surprisingly a remarkable number of BRD2-bound genes including MYC and its target genes were upregulated. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors (TFs) potentially involved in the JQ1 response in BRD2-dependent and independent manner.

2018-06-04 | GSE104481 | GEO

BET bromodomain proteins Brd2, Brd3 and Brd4 selectively regulate metabolic pathways in the pancreatic β-cell

Project description:Displacement of Bromodomain and Extra-Terminal (BET) proteins from chromatin has promise for cancer and inflammatory disease treatments, but roles of BET proteins in metabolic disease remain unexplored. Small molecule BET inhibitors, such as JQ1, block BET protein binding to acetylated lysines, but lack selectivity within the BET family (Brd2, Brd3, Brd4, Brdt), making it difficult to disentangle contributions of each family member to transcriptional and cellular outcomes. Here, we demonstrate multiple improvements in pancreatic β-cells upon BET inhibition with JQ1 or BET-specific siRNAs. JQ1 (50-400 nM) increases insulin secretion from INS-1 cells in a concentration dependent manner. JQ1 increases insulin content in INS-1 cells, accounting for increased secretion, in both rat and human islets. Higher concentrations of JQ1 decrease intracellular triglyceride stores in INS-1 cells, a result of increased fatty acid oxidation. Specific inhibition of both Brd2 and Brd4 enhances insulin transcription, leading to increased insulin content. Inhibition of Brd2 alone increases fatty acid oxidation. Overlapping yet discrete roles for individual BET proteins in metabolic regulation suggest new isoform-selective BET inhibitors may be useful to treat insulin resistant/diabetic patients. Results imply that cancer and diseases of chronic inflammation or disordered metabolism are related through shared chromatin regulatory mechanisms.

2016-03-07 | GSE77450 | GEO

Genome occupancy of NIPBL in mouse P19 teratocarcinoma cells.

2020-01-01 | GSE132784 | GEO

Small-molecule inhibitor JQ1 effect on multiple myeloma cell lines

Project description:Pathologic activation of c-Myc plays a central role in pathogenesis of several neoplasias, including multiple myeloma. However, therapeutic targeting of c-Myc has remained elusive due to its lack of a clear ligand-binding domain. We therefore targeted c-Myc transcriptional function by another means, namely the disruption of chromatin-dependent signal transduction. Members of the bromodomain and extra-terminal (BET) subfamily of human bromodomain proteins (BRD2, BRD3 and BRD4) associate with acetylated chromatin and facilitate transcriptional activation by increasing the effective molarity of recruited transcriptional activators. Notably, BRD4 marks select M/G1 genes in mitotic chromatin for transcriptional memory and direct post-mitotic transcription, via direct interaction with the positive transcription elongation factor complex b (P-TEFb). Because c-Myc is known to regulate promoter-proximal pause release of Pol II, also through the recruitment of P-TEFb, we evaluated the selective small-molecule inhibitor of BET bromodomains, JQ1, as a chemical probe to interrogate the role of BET bromodomains in Myc-dependent transcription and to explore their role as therapeutic targets in c-Myc-driven neoplasias. Duplicate cultures of MM.1S, OPM1 and KMS11 human myeloma cells were treated with either DMSO alone or with JQ1 (500 nM), for 24 hours. Total RNA was extracted and hybridized to Affymetrix human Gene 1.0 ST microarrays (two arrays per treatment per cell line for a total of 12 arrays).

2011-09-01 | E-GEOD-31365 | biostudies-arrayexpress

BRD2 interconnects with BRD3 to facilitate Pol II transcription initiation and elongation to prime promoters for cell differentiation [RNA-seq]

Project description:Understanding the precise functions and relationship of BRD2 with other bromodomain and extraterminal motif (BET) proteins is central for the application of BET-specific and pan inhibitors. Here, we used acute protein degradation and quantitative genomic and proteomic approaches to investigate the primary functions of BRD2 in transcription. We report that BRD2 is required for TAF3-mediated Pol II initiation at low levels of H3K4me3-modified promoters and Pol II elongation by suppressing R-loops. Single and double depletion revealed that BRD2 and BRD3, but not BRD4, redundantly and independently function in Pol II transcription at different promoters and cooperatively occupy enhancers. Interestingly, we found that depletion of BRD2 affects the expression of different genes during differentiation processes, priming with promoter regulation in ES cells. Therefore, our results suggest complex interconnections between BRD2 and BRD3 at promoters to fine-tune Pol II initiation and elongation for control of cell state.

2022-06-13 | GSE160558 | GEO

BRD2 interconnects with BRD3 to facilitate Pol II transcription initiation and elongation to prime promoters for cell differentiation [ChIP-seq]

2022-06-13 | GSE160557 | GEO

BRD2 interconnects with BRD3 to facilitate Pol II transcription initiation and elongation to prime promoters for cell differentiation [ChIA-PET]

2022-06-13 | GSE160556 | GEO