RNA-seq of human donors with severe type 1 interferonopathy due to germline STAT2 gain-of-function
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ABSTRACT:
PROVIDER: PRJEB41073 | ENA |
REPOSITORIES: ENA
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Project description:Severe type 1 interferonopathy due to germline STAT2 gain-of-function
| PRJEB29090 | ENA
Project description:The transcription factor STAT2 is essential for transcriptional activation downstream of the receptors for the innate IFNs -α/β (IFNAR) and -gamma (IFNLR). STAT2 is activated by tyrosine phosphorylation, associating with STAT1 and IRF9 to form the Interferon-Stimulated Gene Factor 3 (ISGF3) to effect gene transcription. Loss-of-function variants in STAT2 increase susceptibility to viral disease. Here a transcriptome study is reported on an individual with severe early-onset neuroinflammatory disease and an elevated IFN signature. The individual had a homozygous missense variant in STAT2 and symptoms consistent with a gain-of-function effect.
2019-11-06 | E-MTAB-7275 | biostudies-arrayexpress
Project description:Patients with type 1 interferonopathies due to mutations in one of 10 genes were recruited over the course of 4 years. All patients had raised levels of interferon stimulated genes as determined by qPCR. A transcriptome analysis was carried out to compare levels of interferon stimulated genes in the patient with a mutation in STAT2, compared to patients with mutations in other interferonopathy genes.
2020-11-03 | E-MTAB-9722 | biostudies-arrayexpress
Project description:Influenza is the common respiratory problem that infects between 5-20% of the US population and results in 30,000 deaths annually. A primary cause of the influenza-associated death is due to secondary bacterial pneumonia. In this study, we investigated the role of STAT2 signaling during influenza and influenza-bacterial super-infection in mice. Herein, we demonstrate that STAT2 signaling is required for viral control, regulation of inflammation, and limiting mortality during influenza single infection. Surprisingly, despite this deficiency in anti-viral immunity, we found increased bacterial control and survival in STAT2 deficient mice during influenza-MRSA super-infection compared to controls. This protection in the absence of STAT2 was associated with accumulation of dual phenotype M1/M2 macrophages, which were required for control of bacterial infection. Together, these results suggest that the STAT2 signaling is involved in suppressing macrophage activation and bacterial control during influenza-bacterial super-infection.
2018-12-26 | GSE119029 | GEO
Project description:STAT2 is an essential transcription factor in type I interferon (IFN) signaling. STAT2 is activated following exposure to IFN stimulation by phosphorylation at tyrosine-690. This post-translational modification permits the assembly and nuclear retention of the ISGF3 complex (consisting of STAT1/STAT2/IRF9) to drive gene transcription. We recently identified STAT2 to be serine phosphorylated in an IFN-dependent manner. The biological significance of these novel phosphorylation events in STAT2 remain to be elucidated. Thus far our data show that serine phosphorylation of STAT2 negatively regulates the biological effects of IFN. In an effort to understand the scope of STAT2 serine phosphorylation in IFN signaling, we conducted comparative microarray analysis to identify a collection of genes that are regulated by phosphorylated Ser734-STAT2 vs. unphosphorylated S734-STAT2 after IFN treatment.
2015-10-01 | GSE57017 | GEO
Project description:Our previous study revealed that the transcription factor STAT2 promoted the growth of colorectal tumors, but the molecular mechanisms by which STAT2 contributes to tumor promotion are still unknown. Given that alterations in the tumor suppressor p53 gene are very common in colorectal cancer and critical in adenoma-carcinoma transition, we investigated whether STAT2 may also be implicated in disease progression when normal p53 function is disabled. We found Stat2 silencing in colon cancer cells deficient in p53 reduced the capacity of tumor cells to migrate and invade in vitro. We also determined that Stat2 silencing impaired tumor cells to metastasize to the liver. To begin to understand how STAT2 contributes to disease progression, we performed RNA-Seq analysis on colon tumor xenografts with the purpose to identify a STAT2 transcriptome. From this study, we identified a subset of STAT2 regulated genes that in future studies will confirm their role in colon carcinogenesis.
2020-11-17 | GSE137155 | GEO
Project description:The samples were derived from STAT2 IP experiments from human fibrosarcoma cells. This experiment involved the transfection of cells with a flag tagged STAT2 and the goal of these experiments is to identify STAT2 binding partners.
2018-10-26 | PXD005008 | Pride
Project description:Excessive type I interferon (IFN?/?) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFN?/?, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFN?/? signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFN?/? signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFN?/? activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.
| S-EPMC7115903 | biostudies-literature
Project description:Type I Interferons (IFN-I) mediate cellular responses to virus infection. IFN-I induce IFN stimulated gene (ISG) expression by phosphorylating STAT1 and STAT2, and together with interferon regulatory factor (IRF)9, form the transcription complex ISGF3 that binds to the interferon-stimulated response element (ISRE) in ISG promoters. As a component of ISGF3 it is clear that STAT2 plays an essential role in the transcriptional responses to IFN-I with a strong dependence on STAT1. Previously, we showed that STAT2 also forms homodimers that interact with IRF9 (STAT2-IRF9) to activate transcription of ISRE containing ISGs in response to IFN-I. Indeed, evidence is accumulating for the existence of a STAT1-independent IFN-I signaling pathway, where STAT2-IRF9 can substitute the role of ISGF3. Here, we provide further insight in the transcriptional regulation and the biological implications of STAT2-IRF9 dependent IFN-I signaling. In human STAT1 KO cells overexpressing human STAT2 (U3C-STAT2) we observed that in response to IFN-I STAT2 homodimers interact with IRF9 to regulate ISG transcription. The IFN-I-induced phosphorylation profile of STAT2 in U3C-STAT2 was prolonged as compared to WT cells (2fTGH), which corresponded with the expression pattern of OAS2 that also depended on IRF9. Subsequent microarray analysis of IFN-I treated 2fTGH and U3C-STAT2 extended our initial observations and identified more than 60 known antiviral ISGs commonly up-regulated in both cell types. The expression profile of these ISGs was delayed and prolonged in U3C-STAT2 as opposed to the early and transient response in 2fTGH. Moreover, U3C-STAT2 were able to restore an antiviral response upon EMCV and VSV infection that was comparable to the response in 2fTGH. Together, our results strongly suggest that an alternative IFN-I-mediated, STAT2-IRF9 dependent signaling pathway exists that can generate an antiviral response without STAT1 and could be beneficial for example against viruses that directly block STAT1 and impair the formation of ISGF3.
2015-09-10 | GSE48313 | GEO
Project description:Type I Interferons (IFN-I) mediate cellular responses to virus infection. IFN-I induces IFN-stimulated gene (ISG) expression by phosphorylating STAT1 and STAT2, and together with interferon regulatory factor (IRF9), form the transcription complex ISGF3 that binds to the interferon-stimulated response element (ISRE) in ISG promoters. As a component of ISGF3, it is clear that STAT2 plays an essential role in the transcriptional responses to IFN-I with a strong dependence on STAT1. Previously, we showed that STAT2 also forms homodimers that interact with IRF9 (STAT2-IRF9) to activate transcription of ISRE-containing ISGs in response to IFN-I. Indeed, evidence is accumulating for the existence of a STAT1-independent IFN-I signaling pathway, where STAT2-IRF9 can substitute the role of ISGF3. Here, we provide further insight in the transcriptional regulation and the biological implications of STAT2-IRF9 dependent IFN-I signaling. In human STAT1 KO cells overexpressing human STAT2 (U3C-STAT2), we observed that in response to IFN-I, STAT2 homodimers interact with IRF9 to regulate ISG transcription. The IFN-I-induced phosphorylation profile of STAT2 in U3C-STAT2 was prolonged as compared to WT cells (2fTGH), which corresponded with the expression pattern of OAS2 that also depended on IRF9. Subsequent microarray analysis of IFN-I treated 2fTGH and U3C-STAT2 extended our initial observations and identified more than 60 known antiviral ISGs commonly up-regulated in both cell types. The expression profile of these ISGs was delayed and prolonged in U3C-STAT2 as opposed to the early and transient response in 2fTGH. Moreover, U3C-STAT2 were able to restore an antiviral response upon EMCV and VSV infection that was comparable to the response in 2fTGH. Together, our results strongly suggest that an alternative IFN-I-mediated, STAT2-IRF9 dependent signaling pathway exists that can generate an antiviral response without STAT1 and could be beneficial for example against viruses that directly block STAT1 and impair the formation of ISGF3.
2015-09-10 | GSE49525 | GEO