Genome-wide maps of STAT1, STAT2 and IRF9 in conjunction with nucleosome occupancy maps at 20 interferon-stimulated gene regions during steady state and after type I interferon stimulation.
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ABSTRACT:
PROVIDER: PRJNA432700 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6666850.fastq.gz | Fastqsanger.gz | |||
| SRR6666851.fastq.gz | Fastqsanger.gz | |||
| SRR6666852.fastq.gz | Fastqsanger.gz | |||
| SRR6666853.fastq.gz | Fastqsanger.gz | |||
| SRR6666854_1.fastq.gz | Fastqsanger.gz |
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Project description:The genome-wide distributions of STAT1, STAT2 and IRF9 in mock and interferon alpha (IFN) stimulated human cells was generated using high throughput sequencing to identify ISGF3 genomic occupancy. In combination, the nucleosome occupancy of 20 select IFN-stimulated gene regions were analyzed by direct selection MNase sequencing to determine the nucleosome positions and changes in nucleosome occupancy levels following IFN treatment over time. IFN stimulation resulted in decreased nucleosome positioning strength, with clear disruption over the course of IFN treatment followed by a return to steady state, and prominently at most ISGF3-bound regions.
2018-07-26 | GSE110067 | 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
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:Interferon (IFN) β and Tumor Necrosis Factor (TNF) α are key players in immunity against pathogens as well as in the development of autoinflammatory and autoimmune diseases. Accordingly, their molecular pathways have attracted much interest as therapeutic targets. Compelling evidence has shown that the antiviral and inflammatory transcriptional response induced by IFNβ is reprogrammed by crosstalk with TNFα. IFNβ typically induces interferon-stimulated genes by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway leading to activation of the canonical ISGF3 transcriptional complex, composed of STAT1, STAT2 and IRF9. The signaling pathways engaged downstream of the combination of IFNβ and TNFα remain elusive, but previous observations suggested the existence of a response independent of STAT1. Here, using genome-wide transcriptional analysis by RNASeq, we observed a broad antiviral and immunoregulatory response initiated in the absence of STAT1 upon IFNβ and TNFα costimulation. Additional stratification of this transcriptional response with respect to the role of STAT2 and IRF9 revealed that they mediate the expression of a wide spectrum of genes. While a subset of genes was regulated by the concerted action of STAT2 and IRF9, other gene sets were independently regulated by STAT2 or IRF9. Collectively, our data supports a model in which STAT2 and IRF9 act through non-canonical parallel pathways to regulate distinct pool of genes in response to IFNβ and TNFα. This study provides novel insights into the molecular pathways leading to antiviral and immunoregulatory gene expression in conditions where elevated levels of both IFNβ and TNFα are present.
2018-02-28 | GSE111195 | GEO
Project description:To further understand the role of phosphorylation in ISGF3- and STAT2/IRF9-mediated constitutive and long-term IFN-I-stimulated transcriptional responses, we performed RNA-Seq and ChIP-Seq, in combination with phosphorylation inhibition and anti-viral experiments. First, we identified a group of ISRE-containing ISGs that were commonly regulated in IFNα treated WT and STAT1-KO cells. Thus, in 2fTGH and Huh7.5 WT cells IFNα-inducible transcription and anti-viral activity relied on the recruitment of the ISGF3 components STAT1, STAT2 and IRF9 in a phosphorylation- and time-dependent manner. Likewise, in ST2-U3C and Huh-STAT1KO cells lacking STAT1, ISG expression correlated with DNA-binding of phosphorylated STAT2/IRF9. This pointed to a dominant role of classical ISGF3 and STAT2/IRF9, and not U-ISGF3 or U-STAT2/IRF9, in the regulation of early and prolonged ISG expression and viral protection, in WT and STAT1-KO cells. In addition, comparative experiments in U3C (STAT1-KO) cells overexpressing all ISGF3 components (ST1-ST2-IRF9-U3C), revealed a threshold-dependent role of U-ISFG3, and potentially U-STAT2/IRF9, in the regulation of constitutive and possibly long-term IFNα-treated ISG expression and anti-viral activity.
2023-11-15 | GSE247724 | GEO
Project description:To further understand the role of phosphorylation in ISGF3- and STAT2/IRF9-mediated constitutive and long-term IFN-I-stimulated transcriptional responses, we performed RNA-Seq and ChIP-Seq, in combination with phosphorylation inhibition and anti-viral experiments. First, we identified a group of ISRE-containing ISGs that were commonly regulated in IFNα treated WT and STAT1-KO cells. Thus, in 2fTGH and Huh7.5 WT cells IFNα-inducible transcription and anti-viral activity relied on the recruitment of the ISGF3 components STAT1, STAT2 and IRF9 in a phosphorylation- and time-dependent manner. Likewise, in ST2-U3C and Huh-STAT1KO cells lacking STAT1, ISG expression correlated with DNA-binding of phosphorylated STAT2/IRF9. This pointed to a dominant role of classical ISGF3 and STAT2/IRF9, and not U-ISGF3 or U-STAT2/IRF9, in the regulation of early and prolonged ISG expression and viral protection, in WT and STAT1-KO cells. In addition, comparative experiments in U3C (STAT1-KO) cells overexpressing all ISGF3 components (ST1-ST2-IRF9-U3C), revealed a threshold-dependent role of U-ISFG3, and potentially U-STAT2/IRF9, in the regulation of constitutive and possibly long-term IFNα-treated ISG expression and anti-viral activity.
2023-11-15 | GSE247723 | GEO
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:Type I interferons (IFN-I) are critical in antimicrobial and antitumor defense. Although IFN-I signal via the interferon-stimulated gene factor 3 (ISGF3) complex consisting of STAT1, STAT2 and IRF9, IFN-I can mediate significant biological effects via ISGF3-independent pathways. For example, absence of STAT1, STAT2 or IRF9 exacerbates neurological disease in transgenic mice with CNS-production of IFN-gamma. Here we determined the role of IFN-I-driven, ISGF3-independent signaling in regulating global gene expression in STAT1, STAT2 or IRF9-deficient murine mixed glial cell cultures (MGCs). Compared with WT, the expression of IFN-gamma-stimulated genes (ISGs) was reduced in number and magnitude in MGCs that lacked STAT1, STAT2 or IRF9. There were significantly fewer ISGs in the absence of STAT1 or STAT2 versus the absence of IRF9. The majority of ISGs regulated in the STAT1-, STAT2- or IRF9-deficient MGCs individually were shared with WT. However, only a minor number of ISGs were common to WT, STAT1-, STAT2- and IRF9-deficient MGCs. While signal pathway activation in response to IFN-gamma was rapid and transient in WT MGCs, this was delayed and prolonged and correlated with increased numbers of ISGs expressed at 12 h versus 4 h IFN-gamma exposure in all three IFN-I-signaling-deficient MGCs. In conclusion, (1) IFN-I can mediate ISG expression in MGCs via ISGF3-independent signaling pathways but with reduced efficiency, with delayed and prolonged kinetics and is more dependent on STAT1 and STAT2 than IRF9, and (2) signaling pathways not involving STAT1, STAT2 or IRF9 play a minor role only in mediating ISG expression in MGCs.
2017-02-15 | E-MTAB-5445 | biostudies-arrayexpress
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:Human cytomegalovirus (CMV) is a highly relevant pathogen, and its rodent counterparts serve as common infection models. Global proteome profiling of rat CMV-infected cells uncovered a pronounced loss of the transcription factor STAT2, which is crucial for interferon signalling. Deletion mutagenesis documented that STAT2 is targeted by the viral protein E27. Cellular and in vitro analyses showed that E27 exploits host-derived Cullin4-RING ubiquitin ligases (CRL4) to induce poly-ubiquitylation and proteasomal degradation of STAT2. Cryo-electron microscopic structure determination revealed how E27 mimics molecular surface properties of cellular CRL4 substrate receptors to displace them from DDB1. Moreover, structural analyses elucidated the mechanism of STAT2 recruitment and indicate that E27-binding additionally disturbs STAT2 activation by occupying the IRF9 binding interface. For the first time, these data provide structural insights into cytomegalovirus-encoded interferon antagonism and establish an atomic model for STAT2 counteraction by CRL4 misappropriation with important implications for viral immune evasion.
2022-12-09 | PXD033639 | Pride