Bromodomain and extra-terminal (BET) inhibitors regulate NK cell biology by inhibiting BRD2 mediated NK cytolytic activity and BRD2/BRD4 mediated inflammatory function
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ABSTRACT:
PROVIDER: PRJNA657865 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12469231_1.fastq.gz | Fastqsanger.gz | |||
| SRR12469231_2.fastq.gz | Fastqsanger.gz | |||
| SRR12469232_1.fastq.gz | Fastqsanger.gz | |||
| SRR12469232_2.fastq.gz | Fastqsanger.gz | |||
| SRR12469233_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
2021-03-16 | GSE156423 | GEO
Project description:The dual bromodomain protein Brd2 is closely related to the basal transcription factor TAFII250, which is essential for cyclin A transactivation and mammalian cell cycle progression. In transgenic mice, constitutive lymphoid expression of Brd2 causes a malignancy most similar to human diffuse large B cell lymphoma. We compare the genome-wide transcriptional expression profiles of these lymphomas with those of proliferating and resting normal B cells. Transgenic tumors reproducibly show differential expression of a large number of genes important for cell cycle control and lymphocyte biology; expression patterns are either tumor-specific or proliferation-specific. Several of their human orthologs have been implicated in human lymphomagenesis. Others correlate with human disease survival time. BRD2 is underexpressed in some subtypes of human lymphoma and these subtypes display a number of similarities to the BRD2-mediated murine tumors. We illustrate with a high degree of detail that cancer is more than rampant cellular proliferation, but involves the additional transcriptional mobilization of many genes, some of them poorly characterized, which show a tumor-specific pattern of gene expression. Experiment Overall Design: 26 samples are included in this series. Sporadic murine E-mu-BRD2 mediated lymphomas are divided into three classes by disease severity and compared to either resting or mitogen-activated B Cells. The resting and activated B Cells are either wildtype or E-mu-BRD2 transgenic. All samples are on the FVB wildtype background.
2008-06-14 | E-GEOD-6136 | biostudies-arrayexpress
Project description:Natural killer (NK) cells are a type of innate lymphocytes that play key roles in immune surveillance against tumors and viral infection. NK cells distinguish abnormal cells from healthy cells by cell-cell interaction with cell surface proteins and then attack target cells via multiple mechanisms involving TRAIL, Fas Ligand, cytokine secretion, perforin, and granzymes. In addition, extracellular vesicles (EVs), including exosomes derived from NK cells (NK-EVs), possess cytotoxic capacity against tumor cells, but their characteristics and regulation by cytokines remain unknown. Here, we report that EVs derived from human NK-92 cells stimulated with IL-15 + IL-21 show enhanced cytotoxic capacity against tumor cells in a granzyme B independent manner. In addition, small RNA-seq and mass spectrometry analyses indicate that miRNA and protein profiles in EVs are altered by cytokine stimulation. We also show NK-EVs are taken up by target cells via macropinocytosis. Collectively, our findings reveal novel characteristics of NK-EVs and the mechanism of their incorporation into target cells.
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Project description:In mouse models, the bromodomain PHD finger transcription factor (BPTF) chromatin remodeling subunit in tumor cells suppresses natural killer (NK) cell antitumor activity. In vitro, BPTF suppresses NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating a conserved function.
2017-04-28 | GSE85756 | GEO
Project description:The dual bromodomain protein Brd2 is closely related to the basal transcription factor TAFII250, which is essential for cyclin A transactivation and mammalian cell cycle progression. In transgenic mice, constitutive lymphoid expression of Brd2 causes a malignancy most similar to human diffuse large B cell lymphoma. We compare the genome-wide transcriptional expression profiles of these lymphomas with those of proliferating and resting normal B cells. Transgenic tumors reproducibly show differential expression of a large number of genes important for cell cycle control and lymphocyte biology; expression patterns are either tumor-specific or proliferation-specific. Several of their human orthologs have been implicated in human lymphomagenesis. Others correlate with human disease survival time. BRD2 is underexpressed in some subtypes of human lymphoma and these subtypes display a number of similarities to the BRD2-mediated murine tumors. We illustrate with a high degree of detail that cancer is more than rampant cellular proliferation, but involves the additional transcriptional mobilization of many genes, some of them poorly characterized, which show a tumor-specific pattern of gene expression. Keywords: disease state analysis
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2023-08-21 | GSE235120 | GEO
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Project description:To dissect Cohesin-independent mechanisms that compartmentalize the mammalian genome, we combined super-resolution imaging and high-resolution chromatin interactome, chromatin binding and accessibility and RNA sequencing analysis. We found that the bromodomain and extra-terminal domain (BET) family protein BRD2 is one key regulator to promote compartmental interactions in the absence of Cohesin. We also identified competitive, rather than cooperative relationship between BET family proteins in shaping the 3D genome organization. This study uncovers new mechanisitc insights on the 3D organization of the mammalian genome.
2022-02-09 | GSE163729 | GEO
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.
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