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Begitt2014 - STAT1 cooperative DNA binding - double GAS polymer model

ABSTRACT: 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.

OTHER RELATED OMICS DATASETS IN: PRJNA213916

SUBMITTER: Michelle Baker

PROVIDER: BIOMD0000000501 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling.

Begitt Andreas A Droescher Mathias M Meyer Thomas T Schmid Christoph D CD Baker Michelle M Antunes Filipa F Knobeloch Klaus-Peter KP Owen Markus R MR Naumann Ronald R Decker Thomas T Vinkemeier Uwe U

Nature immunology 20140112 2

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 diff ...[more]

PMID: 24413774

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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.

Project description:Atherosclerosis is a disease of large and medium-sized muscular arteries and is characterized by vascular inflammation and lipid-laden plaque formation within the intima of the vessel wall. Atherosclerosis is initiated by recruitment of blood leukocytes to the injured vascular endothelium and leads to altered contractility of Vascular Smooth Muscle Cells (VSMCs), acute and chronic luminal obstruction, abnormalities of blood flow and diminished oxygen supply to target organs. The pro-inflammatory pathways activated by Toll-like Receptors (TLRs), and Interferons (IFNs) have been identified as key components of atherogenesis. These pathways culminate in the activation of Signal Transducers and Activator of Transcription (STAT)1-containing complexes ISGF3 and GAF, and Nuclear factor-κB (NFκB) that coordinate expression of multiple chemokines, adhesion molecules, antiviral and antimicrobial proteins in vascular and immune cells. IFN-I and IFN-II participate in signaling cross-talk with TLR4 through combinatorial actions of ISGF3 and GAF with NF-kB leading to enhanced gene expression. Currently it is not clear how this signal integration is regulated at the genome-wide level and if similar mechanisms are activated by the different IFNs in vascular cells as compared to macrophages and dendritic cells. Therefore, we compared genome-wide transcriptional responses of mouse VSMCs, macrophages (BMDMs) and dendritic cells (DCs) in response to IFNα, IFNγ or LPS alone, or after combined treatment using RNA-seq. Consequently, commonly up-regulated genes in VSMCs, BMDMs and DCs could be identified after combined treatment with IFNα+LPS, as well as after combined treatment with IFNγ+LPS. Generally, in all three cell-types combined treatment with IFNα+LPS or IFNγ+LPS resulted in a synergistic increase in gene expression as compared to single treatments. Also, significant functional overlap could be observed between commonly upregulated genes in response to IFNα+LPS and IFNγ+LPS. Using ChIP-seq on chromatin from VSMCs, STAT1 and p65 bound IFNα+LPS and IFNγ+LPS up-regulated genes were identified, containing GAF/GAS, ISGF3/ISRE or NF-kB binding motifs located in promoter regions, but also to up- and downstream genomic regions. Comparing IFNα+LPS and IFNγ+LPS commonly upregulated genes identified a substantial overlap of ISRE-containing genes. Interestingly, STAT1 as part of ISGF3 was shown to bind the promoter of these ISRE-containing genes in response to IFNα as well as IFNγ. Moreover, different binding modes of STAT1-p65 co-binding were detected, including GAS-NFκB, ISRE-NFκB or GAS-ISRE-NFκB, shared by IFNα+LPS and IFNγ+LPS up-regulated genes. This cooperative involvement involved a STAT1-dependent role in the nearby recruitment of p65 already upon single IFNα or IFNγ treatment, via closely located GAS-NFĸB or ISRE-NFĸB binding sites in promoter regions. More important, this STAT1-p65 co-binding was significantly increased upon subsequent LPS exposure and resulted in amplified transcriptional activity of IFNα+LPS and IFNγ+LPS upregulated genes.

Project description:STAT1 gain-of-function (GOF) is a primary immunodeficiency typically characterized by chronic mucocutaneous candidiasis (CMC), recurrent respiratory infections and autoimmunity. Less commonly, also immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX)-like syndromes with CMC, and combined immunodeficiency without CMC have been described. Recently, our group and others have shown that different mutation-specific mechanisms underlie STAT1 GOF in vitro, including faster nuclear accumulation (R274W), and reduced mobility (R321, N574I) to near immobility in the nucleus (T419R) upon IFNγ stimulation. In this work, we evaluated the transcriptomic fingerprint of the aforementioned STAT1 GOF mutants (R274W, R321S, T419R, and N574I) relative to STAT1 wild-type upon IFNγ stimulation in an otherwise isogenic cell model. The majority of genes up-regulated in wild-type STAT1 cells were significantly more up-regulated in cells expressing GOF mutants, except for T419R. In addition to the common interferon regulated genes (IRG), STAT1 GOF mutants up-regulated an additional set of genes, that were in part shared with other GOF mutants or mutation-specific. Overall, R274W and R321S transcriptomes clustered with STAT1 WT, while T419R and N574I had a more distinct fingerprint. We observed reduced frequency of canonical GAS sequences in promoters of genes up-regulated by all the STAT1 GOF mutants, suggesting loss of DNA binding specificity for the canonical GAS consensus. Interestingly, the T419R mutation, expected to directly increase the affinity for DNA, showed the most pronounced effects on the transcriptome. T419R STAT1 dysregulated more non-IRG than the other GOF mutants and fewer GAS or degenerate GAS promotor sequences could be found in the promoter regions of these genes. In conclusion: our work confirms hyperactivation of common sets of IFNγ-induced genes in STAT1 GOF with additional dysregulation of mutation-specific genes, in line with the earlier observed mutation-specific mechanisms. Binding to more degenerate GAS sequences is proposed as a mechanism towards transcriptional dysregulation in R274W, R321S, and N574I. For T419R, an increased interaction with the DNA is suggested to result in a broader and less GAS-specific response. Our work indicates that multiple routes leading to STAT1 GOF are associated with common and private transcriptomic fingerprints, which may contribute to the phenotypic variation observed in vivo.