RNA transcriptome analysis of IRF1 and IRF3 knockout in immortalized primary hepatocytes infected with hepatitis A virus
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE114916 | GEO | 2018/06/01
REPOSITORIES: GEO
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Project description:Hepatitis A virus (HAV), an hepatotropic picornavirus, is a common cause of acute hepatitis in human populations. Although responsible for considerable morbidity and mortality, the mechanisms underlying HAV-mediated liver injury are poorly understood. Ifnar1-/- mice are susceptible to HAV and when infected recapitulate cardinal features of hepatitis A in humans, including serum ALT elevation, hepatocellular apoptosis, and intrahepatic inflammatory cell infiltrates. In contrast, Mavs-/- mice, while equally permissive for infection, experience no liver injury. Previous studies indicate that HAV pathogenesis in Ifnar1-/- mice is dependent upon MAVS-IRF3 signaling, but leave unresolved the role of IRF3-mediated transcription versus non-transcriptional pro-apoptotic activity of activated IRF3 in HAV-induced liver disease. Here, we compared the intrahepatic transcriptomes of HAV-infected naïve Mavs-/- and Ifnar1-/- mice using high throughput RNA sequencing, and characterized IRF3-mediated transcriptional responses associated with hepatocyte apoptosis and liver inflammation.
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Project description:Exposure of macrophages to cytokines and pathogen-associated molecular patterns (PAMPs) can alter their subsequent stimulus responses, in part by epigenetic reprogramming. Our previous studies identified dynamic control of NFκB as a specificity mechanism for inducing hundreds of de novo enhancers in murine macrophages. A second set of hundreds of de novo enhancers are associated with the ISRE DNA binding element of the family of interferon regulatory factors (IRFs). In this project, we have dissected the roles of three endotoxin-responsive IRFs in macrophage de novo enhancer formation. While IRF3 was previously hypothesized to be a chromatin remodeling transcription factor, we found that its genetic requirement for enhancer formation (H3K4me1) is indirect, mediated by its role in type I IFN expression which activates the IRF9-containing ISGF3 transcription factor. However, our analysis shows that ISGF3 is unable to trigger enhancer formation on its own – it must cooperate with IRF1. Timecourse analysis of chromatin accessibility by ATAC-seq reveals that IRF1 plays a major role in the early steps of nucleosome eviction, while its partner ISGF3 then reinforces eviction and H3K4me1 deposition on neighboring nucleosomes. Further studies revealed that IRF1 can also cooperate with the type II IFN-induced GAF transcription factor, generating an additional set of IRF1-GAF-specific enhancers. Finally, global gene expression analysis by RNA-seq reveals that these IRF1-dependent enhancers are associated with potentiated expression of nearby genes in response to secondary immune threat exposure. Together our results reveal unexpected combinatorial coordination of IRF transcription factors in epigenomic reprograming to provide innate immune memory in a manner that is restricted to direct pathogen exposure or type II IFN-associated T-cell immunity, but not secondary innate immune stimulation via type I IFN.
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Project description:Exposure of macrophages to cytokines and pathogen-associated molecular patterns (PAMPs) can alter their subsequent stimulus responses, in part by epigenetic reprogramming. Our previous studies identified dynamic control of NFκB as a specificity mechanism for inducing hundreds of de novo enhancers in murine macrophages. A second set of hundreds of de novo enhancers are associated with the ISRE DNA binding element of the family of interferon regulatory factors (IRFs). In this project, we have dissected the roles of three endotoxin-responsive IRFs in macrophage de novo enhancer formation. While IRF3 was previously hypothesized to be a chromatin remodeling transcription factor, we found that its genetic requirement for enhancer formation (H3K4me1) is indirect, mediated by its role in type I IFN expression which activates the IRF9-containing ISGF3 transcription factor. However, our analysis shows that ISGF3 is unable to trigger enhancer formation on its own – it must cooperate with IRF1. Timecourse analysis of chromatin accessibility by ATAC-seq reveals that IRF1 plays a major role in the early steps of nucleosome eviction, while its partner ISGF3 then reinforces eviction and H3K4me1 deposition on neighboring nucleosomes. Further studies revealed that IRF1 can also cooperate with the type II IFN-induced GAF transcription factor, generating an additional set of IRF1-GAF-specific enhancers. Finally, global gene expression analysis by RNA-seq reveals that these IRF1-dependent enhancers are associated with potentiated expression of nearby genes in response to secondary immune threat exposure. Together our results reveal unexpected combinatorial coordination of IRF transcription factors in epigenomic reprograming to provide innate immune memory in a manner that is restricted to direct pathogen exposure or type II IFN-associated T-cell immunity, but not secondary innate immune stimulation via type I IFN.
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Project description:Exposure of macrophages to cytokines and pathogen-associated molecular patterns (PAMPs) can alter their subsequent stimulus responses, in part by epigenetic reprogramming. Our previous studies identified dynamic control of NFκB as a specificity mechanism for inducing hundreds of de novo enhancers in murine macrophages. A second set of hundreds of de novo enhancers are associated with the ISRE DNA binding element of the family of interferon regulatory factors (IRFs). In this project, we have dissected the roles of three endotoxin-responsive IRFs in macrophage de novo enhancer formation. While IRF3 was previously hypothesized to be a chromatin remodeling transcription factor, we found that its genetic requirement for enhancer formation (H3K4me1) is indirect, mediated by its role in type I IFN expression which activates the IRF9-containing ISGF3 transcription factor. However, our analysis shows that ISGF3 is unable to trigger enhancer formation on its own – it must cooperate with IRF1. Timecourse analysis of chromatin accessibility by ATAC-seq reveals that IRF1 plays a major role in the early steps of nucleosome eviction, while its partner ISGF3 then reinforces eviction and H3K4me1 deposition on neighboring nucleosomes. Further studies revealed that IRF1 can also cooperate with the type II IFN-induced GAF transcription factor, generating an additional set of IRF1-GAF-specific enhancers. Finally, global gene expression analysis by RNA-seq reveals that these IRF1-dependent enhancers are associated with potentiated expression of nearby genes in response to secondary immune threat exposure. Together our results reveal unexpected combinatorial coordination of IRF transcription factors in epigenomic reprograming to provide innate immune memory in a manner that is restricted to direct pathogen exposure or type II IFN-associated T-cell immunity, but not secondary innate immune stimulation via type I IFN.
2024-02-14 | GSE241818 | GEO
Project description:Interferon-regulatory factors (IRFs) are a family of transcription factors (TFs) that play critical roles in translating viral recognition into antiviral responses, including type I IFN production. Dengue virus (DENV) and other clinically important flaviviruses are controlled by functional type I interferon (IFN) responses. Using an experimental model of DENV infection that recapitulates key aspects of the human disease in mice, we demonstrate that while mice lacking the type I IFN receptor (Ifnar1-/-) succumb to DENV infection, mice that are deficient in IRF-3, IRF-5, and IRF-7 – the three transcription factors thought to regulate type I IFN production – survive DENV challenge. Genome-wide RNA-seq analysis of WT, Irf3(-/-)×Irf7(-/-) (DKO), Irf3-/-xIrf5-/-xIrf7-/- (TKO), and Ifnar1-/- (AB6) splenocytes identified minimal type I IFN production but a robust type II IFN (IFN-γ) response in DKO and TKO mice later shown to be dependent on IRF-1. These results reveal a key role for IRF-1 in antiviral defense by activating both type I and II IFN responses during DENV infection.
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Project description:IRF3 is one of the most critical transcription factor in down stream of pattern recognition receptors (such as toll-like receptor and RIG-I-like receptor) signalling pathway. IRF3 is known to induce the expression of type I IFN gene upon virus infection. To furter examine the role of IRF3 in virus-induced gene expression, we preformed microarray analysis in IRF3-/- peritoneal macrophages infected with VSV, and found that IRF3 suppresses the expression of Il12b gene. Peritoneal macrophages from WT of IRF3-/- B6 mice were infected with VSV(1 M.O.I. ) for 6 hous, and then subjected to microarray analysis.
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Project description:PARP7 inhibitors suppress tumor growth in a cell autonomous manner and by activating the immune system through restoring immune signaling. Nevertheless, the targets of PARP7-mediated ADP-ribosylation that regulate innate immune signaling and cancer cell survival remain elusive. Here, we identified PARP7 as a nuclear and cysteine-specific mono-ADP-ribosyltransferase that modified proteins critical for regulating transcription, such as the AP-1 transcription factor FRA1. Loss of FRA1 ADP-ribosylation via PARP7 inhibition by RBN-2397 or mutation of the ADP-ribosylation site C97 increased FRA1 degradation by PSMC3 and the proteasome. We found that the reduction in FRA1 protein levels promoted IRF3 and IRF1-dependent innate immune signaling and CASP8-mediated apoptosis. Furthermore, we demonstrated that high PARP7 expression are critical for inducing apoptosis in FRA1-positive cancer cells using the PARP7 inhibitor. Collectively, our findings highlight the connected roles of PARP7 and FRA1 and emphasize the clinical potential of PARP7 inhibitors for FRA1-driven cancers.
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Project description:Axis inhibition protein 1 (AXIN), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify AXIN acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN maintains the stability of IRF3 by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN undergoes a phase separation triggered by phosphorylated TBK1. This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN RGS domain, enhances the AXIN-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN agonist KYA1797K as an effective antiviral agent.
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Project description:Axis inhibition protein 1 (AXIN), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify AXIN acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN maintains the stability of IRF3 by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN undergoes a phase separation triggered by phosphorylated TBK1. This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN RGS domain, enhances the AXIN-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN agonist KYA1797K as an effective antiviral agent.
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