Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience I
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE226380 | GEO | 2023/04/26
REPOSITORIES: GEO
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Project description:Here we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of cGAS in tauopathy mice diminished microglial IFN-I response, preserved synapse integrity and plasticity, and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation enhanced, while activation of IFN-I downregulated, neuronal MEF2C expression network linked with cognitive resilience in AD.
2023-04-26 | GSE226381 | GEO
Project description:The aims of this study were to 1) identify the earliest transcriptional response of the bovine endometrium to the presence of the conceptus (using RNAseq), 2) investigate if these genes are regulated by interferon tau (IFNT) in vivo, and 3) determine if they are predictive of the pregnancy status of postpartum dairy cows. RNAseq identified 459 differentially expressed genes (DEGs) between pregnant and cyclic endometria on day 16. Quantitative real-time PCR analysis of selected genes revealed PARP12, ZNFX1, HERC6, IFI16, RNF213, and DDX58 expression increased in pregnant compared with cyclic endo- metria on day 16 and were directly upregulated by intrauterine infusion of IFNT in vivo for 2 h (P < 0.05). On day 13 following estrous endometrial expression of nine genes increased [ARHGAP1, MGC127874, LIMS2, TBC1D1, FBXL7, C25H16orf71, LOC507810, ZSWIM4, and one novel gene (ENSBTAT00000050193)] and seven genes decreased (SERBP1, SRGAP2, AL7A1, TBK1, F2RL2, MGC128929, and WBSCR17; P < 0.05) in pregnant compared with cyclic heifers. Of these DEGs, significant differences in expression between pregnant and cyclic endometria were maintained on day 16 for F2RL2, LIMS2, LOC507810, MGC127874, TBC1D1, WBSCR17, and ZSWIM4 (P < 0.05) both their expression was not directly regulated by IFNT in vivo. Analysis of the expression of selected interferon-stimulated genes in blood samples from postpartum dairy cows revealed a significant increase (P < 0.05) in expression of ZXFX1, PARP12, SAMD9, and HERC6 on day 18 following artificial insemination in cows subsequently confirmed pregnant compared with cyclic controls. In conclusion, RNAseq identified a number of novel pregnancy-associated genes in the endometrium of cattle during early pregnancy that are not regulated by IFNT in vivo. In addition, a number of genes that are directly regulated by short term exposure to IFNT in vivo are differentially expressed on day 18 following estrus detection in the blood of postpartum dairy cows depending on their pregnancy status. mRNA profiles of pregnant vs not pregnant cross-bred beef heifers at days 13 and 16 (n=5 per group)
2014-04-01 | E-GEOD-56392 | biostudies-arrayexpress
Project description:The aims of this study were to 1) identify the earliest transcriptional response of the bovine endometrium to the presence of the conceptus (using RNAseq), 2) investigate if these genes are regulated by interferon tau (IFNT) in vivo, and 3) determine if they are predictive of the pregnancy status of postpartum dairy cows. RNAseq identified 459 differentially expressed genes (DEGs) between pregnant and cyclic endometria on day 16. Quantitative real-time PCR analysis of selected genes revealed PARP12, ZNFX1, HERC6, IFI16, RNF213, and DDX58 expression increased in pregnant compared with cyclic endo- metria on day 16 and were directly upregulated by intrauterine infusion of IFNT in vivo for 2 h (P < 0.05). On day 13 following estrous endometrial expression of nine genes increased [ARHGAP1, MGC127874, LIMS2, TBC1D1, FBXL7, C25H16orf71, LOC507810, ZSWIM4, and one novel gene (ENSBTAT00000050193)] and seven genes decreased (SERBP1, SRGAP2, AL7A1, TBK1, F2RL2, MGC128929, and WBSCR17; P < 0.05) in pregnant compared with cyclic heifers. Of these DEGs, significant differences in expression between pregnant and cyclic endometria were maintained on day 16 for F2RL2, LIMS2, LOC507810, MGC127874, TBC1D1, WBSCR17, and ZSWIM4 (P < 0.05) both their expression was not directly regulated by IFNT in vivo. Analysis of the expression of selected interferon-stimulated genes in blood samples from postpartum dairy cows revealed a significant increase (P < 0.05) in expression of ZXFX1, PARP12, SAMD9, and HERC6 on day 18 following artificial insemination in cows subsequently confirmed pregnant compared with cyclic controls. In conclusion, RNAseq identified a number of novel pregnancy-associated genes in the endometrium of cattle during early pregnancy that are not regulated by IFNT in vivo. In addition, a number of genes that are directly regulated by short term exposure to IFNT in vivo are differentially expressed on day 18 following estrus detection in the blood of postpartum dairy cows depending on their pregnancy status.
2014-04-01 | GSE56392 | GEO
Project description:During infection, interferon production leads to upregulation of the interferon-stimulated gene 15 (ISG15) which encodes the ubiquitin-like protein ISG15. ISG15 has a profound role in restricting intracellular infection by viral and bacterial pathogens. It can exert its function either as a free intracellular or extracellular molecule, or as an ubiquitin-like conjugate to substrate proteins in a process called ISGylation. Here, we used a viral-like particle trapping (Virotrap) technology and GST pull down, both coupled to mass spectrometry, to screen for intracellular ISG15-binding proteins. As strongest hit, we identified RNF213, a very large interferon-induced protein targeted to lipid droplets and a genetic risk factor for Moyamoya disease, a rare cerebrovascular disorder. We verified binding of ISG15 and RNF213 with biochemical methods and imaging and found that interferon signaling induces ISGylation and oligomerization of RNF213 on the surface of lipid droplets, acting as a binding platform for ISGylated proteins. Moreover, we showed that knockdown of RNF213 promotes in vitro infection by Listeria monocytogenes, respiratory syncytial virus (RSV) and Coxsackie virus (CV) B3, suggesting a broad antimicrobial activity of RNF213. In contrast, overexpression of RNF213 restricted Listeria infection and was associated with a striking co-localization of RNF213 with intracellular bacteria. Infection experiments in RNF213 deficient mice corroborated these results in vivo, revealing a so far unknown function of RNF213 in the host defense against infection. Together, we report that RNF213 assembles into a binding platform for ISGylated proteins on the surface of lipid droplets, acting as a first step of an antimicrobial cellular pathway that processes ISGylated proteins. Our findings provide novel molecular insights into the ISGylation pathway and point towards an important role of the immune response to infection in the etiology of Moyamoya disease.
2021-08-16 | PXD018345 | Pride
Project description:During infection, interferon production leads to upregulation of the interferon-stimulated gene 15 (ISG15) which encodes the ubiquitin-like protein ISG15. ISG15 has a profound role in restricting intracellular infection by viral and bacterial pathogens. It can exert its function either as a free intracellular or extracellular molecule, or as an ubiquitin-like conjugate to substrate proteins in a process called ISGylation. Here, we used a viral-like particle trapping (Virotrap) technology and GST pull down, both coupled to mass spectrometry, to screen for intracellular ISG15-binding proteins. As strongest hit, we identified RNF213, a very large interferon-induced protein targeted to lipid droplets and a genetic risk factor for Moyamoya disease, a rare cerebrovascular disorder. We verified binding of ISG15 and RNF213 with biochemical methods and imaging and found that interferon signaling induces ISGylation and oligomerization of RNF213 on the surface of lipid droplets, acting as a binding platform for ISGylated proteins. Moreover, we showed that knockdown of RNF213 promotes in vitro infection by Listeria monocytogenes, respiratory syncytial virus (RSV) and Coxsackie virus (CV) B3, suggesting a broad antimicrobial activity of RNF213. In contrast, overexpression of RNF213 restricted Listeria infection and was associated with a striking co-localization of RNF213 with intracellular bacteria. Infection experiments in RNF213 deficient mice corroborated these results in vivo, revealing a so far unknown function of RNF213 in the host defense against infection. Together, we report that RNF213 assembles into a binding platform for ISGylated proteins on the surface of lipid droplets, acting as a first step of an antimicrobial cellular pathway that processes ISGylated proteins. Our findings provide novel molecular insights into the ISGylation pathway and point towards an important role of the immune response to infection in the etiology of Moyamoya disease.
2021-08-16 | PXD018346 | Pride
Project description:The Sp100 component of ND10/PML bodies is a potent tumor suppressor: accelerated senescence and rapid malignant transformation of human fibroblasts through modulation of an embryonic stem cell program. Identifying the functions of proteins, which define specific subnuclear structures and territories, is important for understanding eukaryotic nuclear dynamics. Sp100 is a prototypical protein of ND10/PML bodies and colocalizes with the proto-oncogenic protein PML and Daxx, proteins with critical roles in oncogenic transformation, interferon-mediated viral resistance and response to PML-directed cancer therapeutics. Sp100 isoforms contain PHD, Bromo and HMG domains and are highly sumoylated at ND10/PML bodies, all characteristics suggestive of a role in chromatin mediated gene regulation. However, a clear role for Sp100 in oncogenesis has not been defined. Using isoform-specific knockdown techniques, we show that most human diploid fibroblasts, which lack Sp100, rapidly senesce. microarray analysis of mRNAs expression in BJV (collected at passage 47) and BJ-S (collected at passage 35). In addition, samples were treated for 24 h with 1000 U/ml IFNB. All RNAs were collected in triplicates of biological samples.
2012-12-04 | E-GEOD-20613 | biostudies-arrayexpress
Project description:Identifying the functions of proteins, which define specific subnuclear structures and territories, is important for understanding eukaryotic nuclear dynamics. Sp100 is a prototypical protein of ND10/PML bodies and co-localizes with the proto-oncogenic protein PML and Daxx, proteins with critical roles in oncogenic transformation, interferon-mediated viral resistance and response to PML-directed cancer therapeutics. Sp100 isoforms contain PHD, Bromo and HMG domains and are highly sumoylated at ND10/PML bodies, all characteristics suggestive of a role in chromatin mediated gene regulation. However, no clear role for the Sp100 component of PML bodies in oncogenesis has been defined. Using isoform-specific knockdown techniques, we show that most human diploid fibroblasts, which lack Sp100, rapidly senesce and discuss gene expression changes associated with this rapid senescence.
2012-12-04 | GSE20613 | GEO
Project description:RNF213 is a large, poorly characterized interferon-induced protein. Mutations in RNF213 are associated with predisposition for Moyamoya disease (MMD), a rare cerebrovascular disorder. Recently, RNF213 was found to have broad antimicrobial activity in vitro and in vivo, yet the molecular mechanisms behind this function remain unclear. Using mass spectrometry-based proteomics and validation by real-time PCR we here report that knockdown of RNF213 leads to transcriptional upregulation of MVP and downregulation of CYR61, in line with reported pro- and anti-bacterial activities of these proteins. Knockdown of RNF213 also results in downregulation of DDAH1, which we discover to exert anti-microbial activity against Listeria monocytogenes infection. DDAH1 regulates production nitric oxide (NO), a molecule with both vascular and antimicrobial effects. We show that NO production is reduced in macrophages from RNF213 KO mice, suggesting that RNF213 controls Listeria infection through regulation of DDAH1 transcription and production of NO. Our findings propose a potential mechanism for the antilisterial activity of RNF213 and highlight NO as a potential link between RNF213-mediated immune responses and the development of MMD.
2022-02-17 | PXD027130 | Pride
Project description:Pharmacological inhibition of cGAS with TDI-6570 protected against the synaptic loss and cognitive deficits in P301S tauopathy model, likely via enhancing MEF2C transcriptional network and associated cognitive resilience
2023-04-26 | GSE226383 | GEO
Project description:We previously identified a subset of interferon stimulated genes (ISGs), including Irf7, Irf1, Oas1a and Oas1b, upregulated by a West Nile virus (WNV) infection in wildtype mouse embryo fibroblasts (MEFs) after viral proteins had inhibited type 1 interferon (IFN)-mediated JAK-STAT signaling and also in WNV-infected STAT1-/-, STAT2-/-, IFNAR-/-, IRF3-/-, IRF7-/-, and IRF3/7-/- MEFs. In this study, ISG upregulation by WNV infection was inhibited in RIG-I/MDA5-/- but not in single knockout MEFs. ISGs upregulation was detected in WNV-infected IRF1-/- and IRF5-/- but was minimal in IRF3/5/7-/- MEFs, suggesting redundant IRF involvement. ISG upregulation by WNV infection in IFNAR-/- MEFs was confirmed by RNA-seq. We previously showed that a single proximal interferon stimulated response element (ISRE) in the Oas1a and Oas1b promoters bound the ISGF3 complex during IFN-dependent upregulation. In this study, we used wild-type and mutant promoter luciferase reporter constructs to identify critical regions in the Oas1b and Ifit1 promoters for IFN-independent transcriptional regulation. Two ISREs were required for both promoters. Mutation of these ISREs in an Ifit1 promoter DNA probe reduced in vitro complex formation. An NF-κB inhibitor decreased Ifit1 promoter activity in cells and in vitro complex formation. IRF3 and p50 binding was detected by ChIP for four upregulated ISGs with two proximal ISREs in their promoters. The data indicate that IFN-independent ISG expression of some ISGs is upregulated by two ISREs functioning cooperatively and the binding of a complex consisting of IRF3, 5, and/or 7 and an NF-κB component(s) as well as other as yet unknown factors.
2021-08-31 | GSE182446 | GEO