E-GEOD-44146
Ontology highlight
ABSTRACT:
PROVIDER: E-GEOD-44146 | ExpressionAtlas | 2015-07-10
REPOSITORIES: ExpressionAtlas
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| E-GEOD-44146-analysis-methods.tsv | Tabular | |||
| E-GEOD-44146-atlasExperimentSummary.Rdata | Rdata | |||
| E-GEOD-44146-configuration.xml | Xml | |||
| E-GEOD-44146-percentile-ranks.tsv | Tabular | |||
| E-GEOD-44146.condensed-sdrf.tsv | Tabular |
Items per page: 5 1 - 5 of 107 |
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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>
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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.
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