Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA186428 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR647763.fastq.gz | Fastqsanger.gz | |||
| SRR647764.fastq.gz | Fastqsanger.gz | |||
| SRR647765.fastq.gz | Fastqsanger.gz | |||
| SRR647766.fastq.gz | Fastqsanger.gz | |||
| SRR647767.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Steady-state gene expression is a coordination of synthesis and decay of RNA through epigenetic regulation, transcription factors, miRNAs, and RNA-binding proteins. Here, we present Bru-Seq and BruChase-Seq to assess genome-wide changes to RNA synthesis and stability in human fibroblasts at homeostasis and after exposure to the proinflammatory TNF. The inflammatory response in human cells involves rapid and dramatic changes in gene expression, and the Bru-Seq and BruChase-Seq techniques revealed a coordinated and complex regulation of gene expression both at the transcriptional and posttranscriptional levels. The combinatory analysis of both RNA synthesis and stability using Bru-Seq and BruChase-Seq allows for a much deeper understanding of mechanisms of gene regulation than afforded by the analysis of steadystate total RNA and should be useful in many biological settings. Analysis of the effect of TNF exposure in nascent gene expression and in transcript stability
2013-01-29 | E-GEOD-43440 | biostudies-arrayexpress
Project description:<p>During rheumatoid arthritis (RA), TNF activates fibroblast-like synoviocytes (FLS) inducing in a temporal order a constellation of genes, which perpetuate synovial inflammation. Although the molecular mechanisms regulating TNF-induced transcription are well characterized, little is known about the impact of mRNA stability on gene expression and the impact of TNF on decay rates of mRNA transcripts in FLS. To address these issues we performed RNA sequencing and genome-wide analysis of the mRNA stabilome in RA FLS. We found that TNF induces a biphasic gene expression program: initially, the inducible transcriptome consists primarily of unstable transcripts but progressively switches and becomes dominated by very stable transcripts. This temporal switch is due to: a) TNF-induced prolonged stabilization of previously unstable transcripts that enables progressive transcript accumulation over days and b) sustained expression and late induction of very stable transcripts. TNF- induced mRNA stabilization in RA FLS occurs during the late phase of TNF response, is MAPK-dependent, and involves several genes with pathogenic potential such as IL6, CXCL1, CXCL3, CXCL8/IL8, CCL2, and PTGS2. These results provide the first insights into genome-wide regulation of mRNA stability in RA FLS and highlight the potential contribution of dynamic regulation of the mRNA stabilome by TNF to chronic synovitis.</p>
| phs001371 | dbGaP
Project description:Hayashi2013 - TNF-induced Signaling Dynamics Model (Model A)
Tumor necrosis factor (TNF) plays a crucial role in inflammation and is associated with diseases such as rheumatoid arthritis and cancer. While TNF signaling pathways are well studied, targeted regulation of proinflammatory responses remains a challenge. In this study, Hayashi et al., (2013) developed a computational model to simulate TNF-induced activation of MAP kinase (p38), NF-κB, and proinflammatory gene expression in murine fibroblast cells. The model parameters were optimized to fit experimental data, ensuring accurate representation of TNF signaling dynamics. The simulations using in silico knockouts identified receptor-interacting protein 1 (RIP1) as a key regulator of TNF-driven proinflammatory responses. Experimental validation using Necrostatin-1, a RIP1 inhibitor, confirmed these predictions and demonstrated its potential as a therapeutic target for regulating proinflammatory mediators in TNF-driven diseases.
This model is described in the article:
Hayashi K, Piras V, Tabata S, Tomita M, Selvarajoo K. A systems biology approach to suppress TNF-induced proinflammatory gene expressions. Cell Commun Signal. 2013 Nov 7;11:84. doi: 10.1186/1478-811X-11-84. PMID: 24199619; PMCID: PMC3832246.
Abstract:
Background: Tumor necrosis factor (TNF) is a widely studied cytokine (ligand) that induces proinflammatory signaling and regulates myriad cellular processes. In major illnesses, such as rheumatoid arthritis and certain cancers, the expression of TNF is elevated. Despite much progress in the field, the targeted regulation of TNF response for therapeutic benefits remains suboptimal. Here, to effectively regulate the proinflammatory response induced by TNF, a systems biology approach was adopted.
Results: We developed a computational model to investigate the temporal activations of MAP kinase (p38), nuclear factor (NF)-κB, and the kinetics of 3 groups of genes, defined by early, intermediate and late phases, in murine embryonic fibroblast (MEF) and 3T3 cells. To identify a crucial target that suppresses, and not abolishes, proinflammatory genes, the model was tested in several in silico knock out (KO) conditions. Among the candidate molecules tested, in silico RIP1 KO effectively regulated all groups of proinflammatory genes (early, middle and late). To validate this result, we experimentally inhibited TNF signaling in MEF and 3T3 cells with RIP1 inhibitor, Necrostatin-1 (Nec-1), and investigated 10 genes (Il6, Nfkbia, Jun, Tnfaip3, Ccl7, Vcam1, Cxcl10, Mmp3, Mmp13, Enpp2) belonging to the 3 major groups of upregulated genes. As predicted by the model, all measured genes were significantly impaired.
Conclusions: Our results demonstrate that Nec-1 modulates TNF-induced proinflammatory response, and may potentially be used as a therapeutic target for inflammatory diseases such as rheumatoid arthritis and osteoarthritis.
Figure 2B, obtained from the simulation of TNFR1 Model A, is highlighted here.
This model was curated during the Hackathon hosted by BioMed X GmbH in 2024.
2025-02-19 | MODEL2502170001 | BioModels
Project description:Hayashi2013 - Extended TNF-induced Signaling with Gene Expression Dynamics (Model B)
Tumor necrosis factor (TNF) plays a crucial role in inflammation and is associated with diseases such as rheumatoid arthritis and cancer. While TNF signaling pathways are well studied, targeted regulation of proinflammatory responses remains a challenge. In this study, Hayashi et al., (2013) developed a computational model to simulate TNF-induced activation of MAP kinase (p38), NF-κB, and proinflammatory gene expression in murine fibroblast cells. The model parameters were optimized to fit experimental data, ensuring accurate representation of TNF signaling dynamics. The simulations using in silico knockouts identified receptor-interacting protein 1 (RIP1) as a key regulator of TNF-driven proinflammatory responses. Experimental validation using Necrostatin-1, a RIP1 inhibitor, confirmed these predictions and demonstrated its potential as a therapeutic target for regulating proinflammatory mediators in TNF-driven diseases.
This model is described in the article:
Hayashi K, Piras V, Tabata S, Tomita M, Selvarajoo K. A systems biology approach to suppress TNF-induced proinflammatory gene expressions. Cell Commun Signal. 2013 Nov 7;11:84. doi: 10.1186/1478-811X-11-84. PMID: 24199619; PMCID: PMC3832246.
Abstract:
Background: Tumor necrosis factor (TNF) is a widely studied cytokine (ligand) that induces proinflammatory signaling and regulates myriad cellular processes. In major illnesses, such as rheumatoid arthritis and certain cancers, the expression of TNF is elevated. Despite much progress in the field, the targeted regulation of TNF response for therapeutic benefits remains suboptimal. Here, to effectively regulate the proinflammatory response induced by TNF, a systems biology approach was adopted.
Results: We developed a computational model to investigate the temporal activations of MAP kinase (p38), nuclear factor (NF)-κB, and the kinetics of 3 groups of genes, defined by early, intermediate and late phases, in murine embryonic fibroblast (MEF) and 3T3 cells. To identify a crucial target that suppresses, and not abolishes, proinflammatory genes, the model was tested in several in silico knock out (KO) conditions. Among the candidate molecules tested, in silico RIP1 KO effectively regulated all groups of proinflammatory genes (early, middle and late). To validate this result, we experimentally inhibited TNF signaling in MEF and 3T3 cells with RIP1 inhibitor, Necrostatin-1 (Nec-1), and investigated 10 genes (Il6, Nfkbia, Jun, Tnfaip3, Ccl7, Vcam1, Cxcl10, Mmp3, Mmp13, Enpp2) belonging to the 3 major groups of upregulated genes. As predicted by the model, all measured genes were significantly impaired.
Conclusions: Our results demonstrate that Nec-1 modulates TNF-induced proinflammatory response, and may potentially be used as a therapeutic target for inflammatory diseases such as rheumatoid arthritis and osteoarthritis.
Figure S3, obtained from the simulation of TNFR1 Model B, is highlighted here.
This model was curated during the Hackathon hosted by BioMed X GmbH in 2024.
2025-02-19 | MODEL2502170002 | BioModels
Project description:Steady-state gene expression is a coordination of synthesis and decay of RNA through epigenetic regulation, transcription factors, miRNAs, and RNA-binding proteins. Here, we present Bru-Seq and BruChase-Seq to assess genome-wide changes to RNA synthesis and stability in human fibroblasts at homeostasis and after exposure to the proinflammatory TNF. The inflammatory response in human cells involves rapid and dramatic changes in gene expression, and the Bru-Seq and BruChase-Seq techniques revealed a coordinated and complex regulation of gene expression both at the transcriptional and posttranscriptional levels. The combinatory analysis of both RNA synthesis and stability using Bru-Seq and BruChase-Seq allows for a much deeper understanding of mechanisms of gene regulation than afforded by the analysis of steadystate total RNA and should be useful in many biological settings.
2013-01-29 | GSE43440 | GEO
Project description:Signalling through TNFR1 modulates proinflammatory gene transcription and programmed cell death, and its impairment causes autoimmune diseases and cancer. NEDD4 binding protein 1 (N4BP1) was recently identified as a critical suppressor of proinflammatory cytokine production1, whose mode of action remained unknown. Here, we show that N4BP1 is a novel linear ubiquitin receptor that negatively regulates NFB signalling by its unique dimerization-dependent ubiquitin-binding module. N4BP1 homo-oligomerization strategically positions two non-selective ubiquitin-binding domains, ensuring exclusive recognition of linear ubiquitin. Under proinflammatory conditions, N4BP1 is recruited to the nascent TNFR1 signalling complex where it, through linear ubiquitin binding, regulates stability of the TNFR1 signalling complex and duration of proinflammatory signalling. N4BP1 deficiency accelerates TNF-induced cell death by increasing complex II assembly. Under proapoptotic conditions, Caspase-8 mediates proteolytic processing of N4BP1 and the resulting cleavage fragment of N4BP1, which retains the ability to bind linear ubiquitin, is rapidly degraded by the 26S proteasome, accelerating apoptosis. In summary, our findings demonstrate that N4BP1 dimerization creates a unique linear ubiquitin reader that ensures timely and coordinated regulation of TNFR1-mediated inflammation and cell death.
2024-05-22 | PXD024355 | Pride
Project description:The inflammatory response plays out over time in a reproducible and organized manner after an initiating stimulus. Here we showed that the genes activated in cultured mouse fibroblasts in response to the proinflammatory cytokine tumor necrosis factor can be divided roughly into three groups, each with different induction kinetics. Whereas differential transcription is important in determining the grouping of these genes, differential mRNA stability also exerted strong influence in some cases overriding that of transcriptional control elements on the temporal order of gene expression. mRNA transcripts expressed early after TNF stimulation have abundant AU-rich elements in their 3'-untranslated regions whereas those expressed later are contain fewer AU-rich sequences. Thus mRNA stability and transcriptional control, two intrinsic characteristics of genes, control the kinetics of proinflammatory cytokine-induced gene expression. Experiment Overall Design: The gene expression levels were monitored in the mouse embryonic cells stimulated with TNF for 0, 0.5h, 2h and 12 hours.
2009-01-18 | E-GEOD-14071 | biostudies-arrayexpress
Project description:The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in low-grade adipose tissue inflammation and development of insulin resistance during obesity. In this context, nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), is directly involved and required for the acute activation of the inflammatory gene program. Here we show that the major transactivating subunit of NF?B, v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), is also required for acute TNF-induced suppression of adipocyte genes. Notably, this repression does not involve RELA binding to the associated enhancers but rather loss of cofactors and enhancer RNA (eRNA) selectively from high occupancy sites within super-enhancers. Based on these data we have developed models that with high accuracy predict which enhancers and genes are repressed by TNF in adipocytes. We show that these models are applicable to other cell types where TNF represses genes associated with super-enhancers in a highly cell type-specific manner. Our results propose a novel paradigm for NF?B-mediated repression, whereby NF?B selectively redistributes cofactors from high occupancy enhancers, thereby specifically repressing super-enhancer-associated cell identity genes. Genome-wide assesment of the acute transcriptional response to TNF in human SGBS adipocytes using RNA- ChIP- and DHS-seq. Total RNA-seq and RNAPII-ChIP seq for vehicle and TNF treated adipocytes are available under GSE60462
2015-06-17 | E-GEOD-64233 | biostudies-arrayexpress
Project description:The inflammatory response plays out over time in a reproducible and organized manner after an initiating stimulus. Here we showed that the genes activated in cultured mouse fibroblasts in response to the proinflammatory cytokine tumor necrosis factor can be divided roughly into three groups, each with different induction kinetics. Whereas differential transcription is important in determining the grouping of these genes, differential mRNA stability also exerted strong influence in some cases overriding that of transcriptional control elements on the temporal order of gene expression. mRNA transcripts expressed early after TNF stimulation have abundant AU-rich elements in their 3'-untranslated regions whereas those expressed later are contain fewer AU-rich sequences. Thus mRNA stability and transcriptional control, two intrinsic characteristics of genes, control the kinetics of proinflammatory cytokine-induced gene expression.
2009-01-07 | GSE14071 | GEO
Project description:Cannabinoid 1 receptor (CB1R) expression is upregulated in hepatocytes during viral hepatitis, cirrhosis, and both alcoholic and non-alcoholic fatty liver disease (FLD), whereas its expression is muted under usual physiological conditions. Inhibiting CB1R has been shown to be beneficial in preserving hepatic function in FLD but it is unclear if inhibiting CB1R during an inflammatory response to an acute hepatic injury, such as toxin - induced injury, would also be beneficial. We tested if nullification of hepatocyte-specific CB1R (hCNR1-/-) in mice protects against concanavalin A (Con A) - induced liver injury. We looked for evidence of liver damage and markers of inflammation in response to Con A by measuring liver enzyme levels and proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, IL-17) in serum collected from hCNR1-/- and control mice. We observed a shift to the right in the dose-response curve for liver injury and inflammation in hCNR1-/- mice. We also found less inflammatory cell infiltration and focal necrosis in livers of hCNR1-/- mice compared to controls, resulting from downregulated apoptotic markers. This anti-apoptotic mechanism results from increased activation of nuclear factor kappa B (NF-κB), especially membrane-bound TNF-α, via downregulated TNF-α receptor 2 (TNFR2) transcription levels. We also found that CB1R in hepatocytes regulated liver inflammation - related gene transcription. Collectively, these findings provide insight into involvement of CB1R in the pathogenesis of acute liver injury.
2020-12-22 | GSE148309 | GEO