Aguilera2017 - Model for IRF7 circuit
Ontology highlight
ABSTRACT:
SUBMITTER: 
Luis Ubaldo Aguilera de Lira
PROVIDER: MODEL1608100001 | BioModels | 2017-03-17
REPOSITORIES: BioModels
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Project description:Model destription:
The model describes the stochastic dynamics of two variables, protein and mRNA of a gene with constitutive expression.
Publication:
A New Efficient Approach to Fit Stochastic Models on the Basis of High-throughput Experimental Data Using a Model of IRF7 Gene Expression as Case Study
Authors
Luis U. Aguilera, Christoph Zimmer and Ursula Kummer.
2017-03-17 | MODEL1608100000 | BioModels
Project description:The glucocorticoid (GC) receptor (GR) is essential in development and inflammation. Healthy GRdim/dim mice with reduced dimerization propensity due to a point mutation (A465T) at the dimer interface of the GR DNA binding domain (DBD) (here GRD/D) have helped to define GR monomer and dimer functions of GR. Since GRD/D retains residual dimerization capacity, we generated the dimer-nullifying double mutant GRD+L/D+L mice, featuring an additional mutation (I634A) in the ligand binding domain (LBD) of GR. These mice are perinatally lethal, as are GRL/L mice, displaying improper lung and skin formation. We used embryonic fibroblasts, high and low doses of dexamethasone (Dex), nuclear translocation, RNAseq, dimerization assays and ligand binding assays (and Kd values), we suggest that the lethal phenotype is due to insufficient ligand binding. The data suggest cross talk between GR dimerization potential and ligand affinity. We conclude that a mutation as subtle as this I634A, at a position not directly involved in ligand interactions senso stricto, can thus still influence ligand binding and have a lethal outcome.
2021-11-29 | GSE189356 | GEO
Project description:The glucocorticoid (GC) receptor (GR) is essential in development and inflammation. Healthy GRdim/dim mice with reduced dimerization propensity due to a point mutation (A465T) at the dimer interface of the GR DNA binding domain (DBD) (here GRD/D) have helped to define GR monomer and dimer functions of GR. Since GRD/D retains residual dimerization capacity, we generated the dimer-nullifying double mutant GRD+L/D+L mice, featuring an additional mutation (I634A) in the ligand binding domain (LBD) of GR. These mice are perinatally lethal, as are GRL/L mice, displaying improper lung and skin formation. We used embryonic fibroblasts, high and low doses of dexamethasone (Dex), nuclear translocation, RNAseq, dimerization assays and ligand binding assays (and Kd values), we suggest that the lethal phenotype is due to insufficient ligand binding. The data suggest cross talk between GR dimerization potential and ligand affinity. We conclude that a mutation as subtle as this I634A, at a position not directly involved in ligand interactions senso stricto, can thus still influence ligand binding and have a lethal outcome.
2021-12-03 | GSE189620 | GEO
Project description:Transcriptional response to virus infection in mice lacking type I and type III signaling The transcriptional response to virus infection is thought to be predominantly induced by interferon (IFN) signaling. Here we demonstrate that, in the absence of IFN signaling, an IFN-like transcriptome is still maintained. This transcriptional activity is mediated from IFN-stimulated response elements (ISREs) that bind to both the IFN stimulated gene factor 3 (ISGF3) as well as to IFN response factor 7 (IRF7). Through a combination of both in vitro biochemistry and in vivo transcriptional profiling, we have dissected what constitutes IRF-specific, ISGF3-specific, or universal ISREs. Taken together, the data presented here suggests that IRF7 can induce an IFN-like transcriptome in the absence of type-I or -III signaling and therefore provides a level of redundancy to cells to ensure the induction of the antiviral state. Mouse: Infections were performed in triplicate and lungs from each condition were pooled for total RNA isolation. Human: Analysis of IRF7 transcriptome in U3A cell line was performed in duplicates.
2010-10-15 | E-GEOD-24695 | biostudies-arrayexpress
Project description:Transcriptional response to virus infection in mice lacking type I and type III signaling The transcriptional response to virus infection is thought to be predominantly induced by interferon (IFN) signaling. Here we demonstrate that, in the absence of IFN signaling, an IFN-like transcriptome is still maintained. This transcriptional activity is mediated from IFN-stimulated response elements (ISREs) that bind to both the IFN stimulated gene factor 3 (ISGF3) as well as to IFN response factor 7 (IRF7). Through a combination of both in vitro biochemistry and in vivo transcriptional profiling, we have dissected what constitutes IRF-specific, ISGF3-specific, or universal ISREs. Taken together, the data presented here suggests that IRF7 can induce an IFN-like transcriptome in the absence of type-I or -III signaling and therefore provides a level of redundancy to cells to ensure the induction of the antiviral state.
2010-10-15 | GSE24695 | GEO
Project description:Eukaryotic protein homeostasis (proteostasis) is largely dependent on the action of highly conserved Hsp70 molecular chaperones. Recent evidence indicates that apart from conserved molecular allostery, Hsp70 proteins retained and adapted throughout the evolution the ability to assemble as functionally relevant ATP-bound dimers. Here we have compared the ATP-dependent dimerization of DnaK, human stress-inducible Hsp70, Hsc70 and BiP Hsp70 proteins showing that their dimerization propensities differ with stress-inducible Hsp70 being predominantly dimeric in the presence of ATP. The structural analyses using hydrogen/deuterium exchange mass spectrometry, native electrospray ionization mass spectrometry, chemical cross-linking and small-angle X-ray scattering revealed that stress-inducible Hsp70 assembles in solution as an antiparallel dimer with the intermolecular interface closely resembling the ATP-bound dimer interfaces captured in DnaK and BiP crystal structures. ATP-dependent dimerization of stress-inducible Hsp70 is necessary for its efficient interaction with Hsp40 as shown by experiments with dimerization-deficient mutants. Moreover, dimerization of ATP-bound Hsp70 is required for its participation in high molecular weight protein complexes detected ex vivo supporting its functional role in vivo. As human cytosolic Hsp70 has the ability to interact with tetratricopeptide repeat (TPR) domain containing co-chaperones, we tested the interaction of Hsp70 ATP-dependent dimer with Chip and Tomm34 co-chaperones. While Chip associates with intact Hsp70 dimer to form a larger complex, binding of Tomm34 disrupts Hsp70 dimer and this event plays an important role in Hsp70 activity regulation. In summary, this study provides structural evidence of robust ATP-dependent antiparallel dimerization of human inducible Hsp70 protein and suggests novel role of TPR domain co-chaperones in multichaperone complexes involving Hsp70 ATP-bound dimers.
2018-12-11 | PXD010069 | Pride
Project description:Glucocorticoids control expression of a large number of genes after binding to the glucocorticoid receptor (GR). Transcription may be regulated either by binding of the GR dimer to DNA regulatory elements or by protein-protein interactions of GR monomers with other transcription factors. Although the type of regulation for a number of individual target genes is known, the relative contribution of both mechanisms to the regulation of the entire transcriptional program remains elusive. To study the importance of GR dimerization in regulation of gene expression, we performed gene expression profiling in liver of prednisolone-treated wild type (WT) and genetically engineered mice that have lost the ability to form GR-dimers (GRdim). Mice carrying a wild type (WT) glucocorticoid receptor or a dimerization-defective glucocorticoid receptor (GRdim) were treated subcutaneous with vehicle or prednisolone (1mg/kg) and sacrificed 150 minutes later. From the livers of these mice total RNA was extracted, processed and hybridized on Affymetrix microarrays. In total 24 mice (6 vehicle-treated WT mice, 6 prednisolone-treated WT mice, 6 vehicle-treated GRdim mice and 6 prednisolone-treated GRdim mice) were included in the study.
2010-06-08 | E-GEOD-21048 | biostudies-arrayexpress
Project description:Begitt2014 - STAT1 cooperative DNA binding - double GAS polymer model
The importance of STAT1-cooperative DNA binding in type 1 and type 2 interferon signalling has been studies using experimental and modelling approaches. The authors have developed two ODE models to describe STAT1 binding to short promoter regions of DNA, namely "single GAS polymer model" and "double GAS polymer model" considering binding to single or double GAS sites, respectively. The length of DNA in the single GAS model was three sites and four sites in double GAS model. This model correspond to the "double GAS polymer model".
This model is described in the article:
STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling.
Begitt A, Droescher M, Meyer T, Schmid CD, Baker M, Antunes F, Owen MR, Naumann R, Decker T, Vinkemeier U
Nat Immunol. 2014 Feb;15(2):168-76.
Abstract:
STAT1 is an indispensable component of a heterotrimer (ISGF3) and a STAT1 homodimer (GAF) that function as transcription regulators in type 1 and type 2 interferon signaling, respectively. To investigate the importance of STAT1-cooperative DNA binding, we generated gene-targeted mice expressing cooperativity-deficient STAT1 with alanine substituted for Phe77. Neither ISGF3 nor GAF bound DNA cooperatively in the STAT1F77A mouse strain, but type 1 and type 2 interferon responses were affected differently. Type 2 interferon-mediated transcription and antibacterial immunity essentially disappeared owing to defective promoter recruitment of GAF. In contrast, STAT1 recruitment to ISGF3 binding sites and type 1 interferon-dependent responses, including antiviral protection, remained intact. We conclude that STAT1 cooperativity is essential for its biological activity and underlies the cellular responses to type 2, but not type 1 interferon.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000501
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2024-09-02 | BIOMD0000000501 | BioModels
Project description:Begitt2014 - STAT1 cooperative DNA binding - single GAS polymer model
The importance of STAT1-cooperative DNA binding in type 1 and type 2 interferon signalling has been studies using experimental and modelling approaches. The authors have developed two ODE models to describe STAT1 binding to short promoter regions of DNA, namely "single GAS polymer model" and "double GAS polymer model" considering binding to single or double GAS sites, respectively. The length of DNA in the single GAS model was three sites and four sites in double GAS model. This model correspond to the "single GAS polymer model".
This model is described in the article:
STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling.
Begitt A, Droescher M, Meyer T, Schmid CD, Baker M, Antunes F, Owen MR, Naumann R, Decker T, Vinkemeier U
Nat Immunol. 2014 Feb;15(2):168-76.
Abstract:
STAT1 is an indispensable component of a heterotrimer (ISGF3) and a STAT1 homodimer (GAF) that function as transcription regulators in type 1 and type 2 interferon signaling, respectively. To investigate the importance of STAT1-cooperative DNA binding, we generated gene-targeted mice expressing cooperativity-deficient STAT1 with alanine substituted for Phe77. Neither ISGF3 nor GAF bound DNA cooperatively in the STAT1F77A mouse strain, but type 1 and type 2 interferon responses were affected differently. Type 2 interferon-mediated transcription and antibacterial immunity essentially disappeared owing to defective promoter recruitment of GAF. In contrast, STAT1 recruitment to ISGF3 binding sites and type 1 interferon-dependent responses, including antiviral protection, remained intact. We conclude that STAT1 cooperativity is essential for its biological activity and underlies the cellular responses to type 2, but not type 1 interferon.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000500
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2024-09-02 | BIOMD0000000500 | BioModels