Bromodomain Containing Protein 4 (BRD4) Regulates Inducible Expression Of Its Interactome In The Innate Response To Respiratory Syncytial Virus
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE179353 | GEO | 2021/10/01
REPOSITORIES: GEO
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Project description:Respiratory Syncytial Virus (RSV) causes severe inflammation and airway pathology in children and the elderly by infecting the epithelial cells of the upper and lower respiratory tract. RSV replication is sensed by intracellular pattern recognition receptors upstream of the IRF and NF-$\upkappa$B transcription factors. These proteins coordinate an innate inflammatory response via Bromodomain containing protein 4 (BRD4), a protein that functions as a scaffold for unknown transcriptional regulators. To better understand the pleiotropic regulatory function of BRD4, we examine the BRD4 interactome and identify how RSV infection dynamically alters it. To accomplish these goals, we leverage native immunoprecipitation and Parallel Accumulation – Serial Fragmentation (PASEF) mass spectrometry to examine BRD4 complexes isolated from human alveolar epithelial cells in the absence or presence of RSV infection. In addition, we explore the role of BRD4's acetyl-lysine binding bromodomains in mediating these interactions by using a highly selective competitive bromodomain inhibitor. We identify 101 proteins that are significantly enriched in the BRD4 complex and are responsive to both RSV-infection and BRD4 inhibition. These proteins are highly enriched in transcription factors and transcriptional coactivators. Among them, we identify members of the AP1 transcription factor complex, a complex important in innate signaling and cell stress responses. We independently confirm the BRD4/AP1 interaction in primary human small airway epithelial cells. We conclude that BRD4 recruits multiple transcription factors during RSV infection in a manner dependent on acetyl-lysine binding domain interactions. This data suggests that BRD4 recruits transcription factors to target its RNA processing complex to regulate gene expression in innate immunity and inflammation.
2021-03-17 | PXD023983 | Pride
Project description:we examine the effect of RSV infection in human small airway epithelial cells (hSAECs)
2021-02-26 | GSE167486 | GEO
Project description:Inducible cell stress programs in basal epithelial cells shape repair and host defense pathways in mucosal surfaces. Previously, we discovered that expression of the core SWI/SNF complex ATPase, SMARCA4/Brg1, is required for genomic organization supporting a fully differentiated epithelial state, regulating cellular plasticity, paracrine mesenchymal signaling and anti-viral response. Here, we observe that SMARCA4 expression is intrinsically engaged with IFN response genes and dynamically engages the atypical histone acetyltransferase, BRD4, upon RSV infection, an association required for intrinsic immunity. To investigate the mechanisms how the SMARCA4 BRD4 complex functions in intrinsic immunity, we performed Cleavage Under Targets and Release Using Nuclease (CUT&RUN) of BRD4 binding in wild type (WT) and SMARCA4 knockdown (KD) small airway epithelial cells in mock- or RSV-infected states. In mock-infected cells, 4,017 high confidence BRD4 peaks are identified that localize to the gene bodies controlling motility programs. By contrast, RSV replication repositions BRD4 to 2,339 regions, upstream of transcription start sites in genes controlling inducible cytokine, cell adherence and anti-viral programs. RSV redistributes BRD4 into super enhancers regulating immune response-associated long noncoding RNAs. BRD4 binding is not affected by SMARCA4 KD in mock-infected cells, but BRD4 recruitment is reduced on 739 peaks after RSV infection, including superenhancers. These data extend the complex interrelationship between the SWI/SNF ATPases and that of the BRD4 bromodomain epithelial progenitors linking cell state and innate immunity.
2024-08-30 | GSE273399 | GEO
Project description:Bromodomain Containing Protein 4 (BRD4) Regulates Inducible Expression Of Its Interactome In The Innate Response To Respiratory Syncytial Virus
| PRJNA743332 | ENA
Project description:Bromodomain-containing protein 4 (BRD4) is an important epigenetic reader which promotes gene transcription to modulate cell-specific functions and is under intensive investigation for its potential as an anti-tumor therapeutic target. However, the role of BRD4 in non-transformed cells remains unclear. Here we demonstrate that BRD4 is required for the expression of epithelial-specific genes and suppression of stem cell-like properties by binding to the distal regions of epithelial-related genes. Moreover, BRD4 occupancy correlates with enhancer activity and enhancer RNA (eRNA) transcription of epithelial differentiation-specific genes. Interestingly, we show that BRD4 perturbation regulates the expression of Grainy Head-like transcription factor, GRHL3, whose depletion partially mimics BRD4 inhibition and blocks differentiated phenotype. By binding to the distal regions of GRHL3, BRD4 promotes RNA polymerase-II occupancy and thus affects eRNA transcription. Altogether, these findings provide evidence that BRD4 promotes a differentiated epithelial phenotype in non-transformed mammary cells at least in part through the activation of GRHL3 expression.
2016-10-06 | GSE72931 | GEO
Project description:Bromodomain-containing protein 4 (BRD4) is an important epigenetic reader which promotes gene transcription to modulate cell-specific functions and is under intensive investigation for its potential as an anti-tumor therapeutic target. However, the role of BRD4 in non-transformed cells remains unclear. Here we demonstrate that BRD4 is required for the expression of epithelial-specific genes and suppression of stem cell-like properties by binding to the distal regions of epithelial-related genes. Moreover, BRD4 occupancy correlates with enhancer activity and enhancer RNA (eRNA) transcription of epithelial differentiation-specific genes. Interestingly, we show that BRD4 perturbation regulates the expression of Grainy Head-like transcription factor, GRHL3, whose depletion partially mimics BRD4 inhibition and blocks differentiated phenotype. By binding to the distal regions of GRHL3, BRD4 promotes RNA polymerase-II occupancy and thus affects eRNA transcription. Altogether, these findings provide evidence that BRD4 promotes a differentiated epithelial phenotype in non-transformed mammary cells at least in part through the activation of GRHL3 expression.
2016-10-06 | GSE72932 | GEO
Project description:Bromodomain-containing Protein 4 (BRD4) is a transcriptional regulator associated with cancer biology, inflammation, and fibrosis. In airway viral infection, non-toxic BRD4-specific inhibitors (BRD4i) block the release of pro- inflammatory cytokines and prevent downstream remodeling. Although the chromatin modifying functions of BRD4 in inducible gene expression have been extensively investigated, its roles in post-transcriptional regulation are not as well understood. Based on its interaction with transcriptional elongation complex and spiceosome, we hypothesize that BRD4 is a functional regulator of RNA processing. To address this question, we combine data-independent analysis - parallel accumulation-serial fragmentation (diaPASEF) with RNA-sequencing to achieve deep coverage of the proteomic and transcriptomic landscape of human small airway epithelial cells exposed to viral challenge and treated with BRD4i. The transcript-level data was further interrogated for alternative splicing analysis, and the resulting data sets were correlated to identify pathways subject to post-transcriptional regulation. We discover that BRD4 regulates alternative splicing of key genes, including Interferon-related Developmental Regulator 1 (IFRD1) and X-Box Binding Protein 1 (XBP1), related to the innate immune response and the unfolded protein response, respectively. These findings extend the actions of BRD4 in control of post-transcriptional RNA processing.
2023-06-13 | PXD039212 | Pride
Project description:Human bronchial epithelial cells (BEAS-2B cells) were treated with RSV at 1.0 MOI for 4 and 24 hours or control (vehicle-treated for 4 hours). Global gene expression was measured by Affy Hu133 plus 2.0 microarray chips. Experiment Overall Design: 4 controls (vehicle-treated for 4 hours) Experiment Overall Design: 4 RSV-treated for 4 hours Experiment Overall Design: 4 RSV-treated for 24 hours
2007-10-02 | E-GEOD-3397 | biostudies-arrayexpress
Project description:Epithelial cells are the primary target of respiratory viral infections and play a pivotal role in virus-induced lung inflammation and in anti viral immune response. A common signal for the presence of viral infections and induction of inflammation is recognition of double stranded RNA (dsRNA). Thus far, there has not been a high-throughput transcrptome analysis of RSV- or dsRNA-induced genes in primary human bronchial epithelial cells (PHBE), nor there has been a comparison between dsRNA- and RSV-induced genes. To establish the transcriptome profiles and to determine the contribution of dsRNA in the induction of inflammation during respiratory virus infection, we compared the gene expression profiles of PHBE cells that were infected with RSV or were treated with dsRNA. Our transcriptome analysis showed that RSV infection and and dsRNA treatment induced up-regulation of 2024 and 159 genes in PHBE respectively. Comparison of genes revealed that RSV and dsRNA commonly induced 80 genes in PHBE cells. The common up-regulated genes were functionally grouped in multiple response pathways involved in inflammation and immune responses. Interestingly, there were several previously unreported genes that were up-regulated in primary human epithelial cells that are relevant to a TH2 allergic phenotype. This comparison of a high-throughput gene expression study offers a comprehensive view of transcriptional changes induced by dsRNA and RSV, and importantly compares dsRNA-induced genes with RSV-induced genes in PHBE cells.
2009-11-16 | GSE12144 | GEO
Project description:Transcriptional elongation by RNA polymerase II (Pol II) is regulated by positive transcription elongation factor b (P-TEFb) in association with Bromodomain-containing protein 4 (BRD4). We used genome-wide chromatin immunoprecipitation sequencing in primary human CD4+ T cells to reveal that BRD4 co-localizes with Ser2-phosphorylated Pol II (Pol II Ser2) at both enhancers and promoters of active genes. Disruption of bromodomain:histone acetylation interactions by JQ1, a small-molecule bromodomain inhibitor, resulted in decreased BRD4 binding, reduced Pol II Ser2, and reduced expression of lineage-specific genes in primary human CD4+ T cells. A large number of JQ1-disrupted BRD4 binding regions exhibited di-acetylated H4 (lysine-5 and -8) and H3K27 acetylation (H3K27ac), which correlated with the presence of histone acetyltransferases and deacetylases. Genes associated with BRD4/H3K27ac co-occupancy exhibited significantly higher activity than those associated with H3K27ac or BRD4 binding alone. Comparison of BRD4 binding in T cells and in human embryonic stem cells revealed that enhancer BRD4 binding sites were predominantly lineage-specific. Our findings suggest that BRD4-driven Pol II phosphorylation at serine 2 plays an important role in regulating lineage-specific gene transcription in human CD4+ T cells. Examination of BRD4, total Pol II, serine 2 phosphorylated Pol II and serine 5 phosphorylated Pol II binding in CD4+ T cells (with and without JQ1 treatment) and BRD4 binding in human embryonic stems cell; PolyA RNA expression in CD4+ T cells( with and without JQ1 treatment) using RNA-seq
2012-11-14 | E-GEOD-33281 | biostudies-arrayexpress