ATF3 is a central regulator of interferon-beta and interferon-stimulated genes during the innate immune response
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE61055 | GEO | 2015/09/07
SECONDARY ACCESSION(S): PRJNA260167
REPOSITORIES: GEO
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Project description:This study shows that in the absence of Atf3, primary mouse macrophages display significantly greater basal and PRR-inducible IFNβ expression. This regulation appears to be directly on the level of Ifnb1 transcription mediated by ATF3 binding proximal to the Ifnb1 promoter under basal condition. The ATF3 expression was demonstrated to be type I IFN-inducible in both human and mouse immune cells. A subset of 36 genes downstream of IFNAR signalling were modulated in an ATF3-dependent manner.The regulation of IFN responses by ATF3 had significant relevance on in vitro viral infection. Together these findings demonstrate that ATF3 is an important regulatory handbrake that limits the magnitude of IFN responses on multiple levels; basal Ifnb1 expression; PRR-inducible IFNβ; and the expression of specific ISGs. 12 samples
2015-09-07 | E-GEOD-61055 | biostudies-arrayexpress
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2017-04-24 | GSE87386 | GEO
Project description:Type I interferons (IFN-I) are transiently induced during infections, but were reported to be produced in the thymus at steady state. We found that developing thymocytes displayed an IFN-I signature that was mainly dependent on IFN-β. Using Ifnb1 reporter mouse strains, we observed IFN-β expression in a small population of medullary thymic epithelial cells (mTEC), which was AIRE-dependent and peaked at 2-3 weeks of age. To study the cellular response to thymic IFN, we used a Mx1gfp reporter mouse strain and found that the IFN response in T cells and myeloid cells was abrogated by IFNaR deficiency, whereas the response in B cells and dendritic cells was dependent on both IFNaR and IFNlR. Furthermore, single-cell RNAseq analysis revealed dramatic transcriptional changes in all thymic APCs in IFNaR/IFNlR deficient mice, and a loss of CCR7+ cDC1 cells. Together, these results show that steady state IFN-I and IFN-III signaling drives a gene-expression program in thymic APCs that shapes the thymic microenvironment.
2024-09-09 | GSE192715 | GEO
Project description:The role of astrocytes in innate immunity during viral infections of the central nervous system (CNS) remains to be fully elucidated. Here, we demonstrate that type I interferon (IFN) receptor (IFNAR) signaling in astrocytes regulates blood-brain barrier permeability and protects the cerebellum from infection and immunopathology. Mice with astrocytes lacking IFNAR signaling showed decreased survival after West Nile virus infection that was not due to expanded viral tropism or increased replication. Pattern recognition receptors and IFN-stimulated genes (ISGs) had higher basal and IFN-induced expression in human and mouse cerebellar astrocytes compared to cerebral cortical astrocytes. Our data identify cerebellar astrocytes as key responders to viral infection and highlight distinct innate immune programs in astrocytes from evolutionarily disparate regions of the CNS.
2016-12-01 | GSE89476 | GEO
Project description:We provide evidence that the Unc-51-like kinase 1 (ULK1) is phosphorylated and activated during engagement of the Type I IFN receptor. Our studies demonstrate that the function of ULK1 controls expression of key interferon stimulated genes (ISGs) that mediate important biological functions, including anti-viral and antineoplastic responses. Total RNA was isolated from untreated and IFNβ-treated Ulk1/2+/+ and Ulk1/2-/- mouse embryonic fibroblasts (MEFs). Cells were treated for 6 hours with or without mouse IFNβ (2500 IU/ml).
2014-08-26 | E-GEOD-60778 | biostudies-arrayexpress
Project description:Cancer associated fibroblasts (CAFs) play an important role in initiating and promoting epithelial cancers. The specific chromatin modifications involved in CAF activation remain to be elucidated. CSL, a constitutive transcriptional repressor and mediator of canonical Notch signaling, functions as a direct negative regulator of CAF effector genes and suppresses cancer/stromal cell expansion. We find that ATF3, a key stress responsive transcriptional repressor up-regulated in the acute UVA response of skin fibroblasts, is down-modulated in stromal cells of premalignant skin SCC lesions similarly to CSL. Increased ATF3 expression counteracts the consequences of compromised CSL, binding to a large set of overlapping target genes. At low basal levels, ATF3 converges with CSL in negative control of CAF activation, binding to a very small number of genomic loci that encompass mostly non-coding RNAs and pseudogenes. Silencing of ATF3 results in chromatin modifications and Pol II recruitment to many loci to which ATF3 does not bind, which are similarly affected by CSL silencing. The observed changes are of functional significance, as Bet inhibitors, which unlink activated chromatin from the basic transcription apparatus, have opposite effects of ATF3 or CSL silencing on all tested CAF effector genes. They exert a similar impact on clinically-derived CAFs both in vitro and upon topical in vivo treatment. Thus, ATF3 converges with CSL in global chromatin control of CAF activation with their loss eliciting epigenetic changes amenable to cancer and stroma-focused intervention.
2017-06-30 | GSE81403 | GEO
Project description:Maintenance of genetic integrity is essential for survival of all organisms. Activating transcription factor 3 (ATF3) is a member of the c-AMP response element binding (CREB)/ATF family of transcription factors, and is highly inducible by various stress conditions including DNA damage. However, downstream targets and molecular basis underlying pleiotropic effects of ATF3 on the cell fate have been largely unknown. To identify ATF3 targets in the human genome, we carried out chromatin immunoprecipitation-microarray (ChiP-on-chip) and knockdown-expression profiling analysis using two models where ATF3 was either transiently induced or constitutively expressed. We show that ATF3 binds to an unexpectedly large number of targets; 5,984 promoters in HCT116 cells treated with an alkylating agene methyl methanesulfonate (MMS) and 1,423 promoters in LNCaP cells constitutively expressing ATF3. Importantly, targets of MMS-induced ATF3 are highly enriched not only for CREB/ATF motifs but also for binding sites of several stress sensors including DDIT3/CHOP, Egr1, and c-Ets which are concomitantly induced by MMS. Stress-induced ATF3 affects broad but select biological processes including cell cycle, cell death, adhesion, biosynthesis, and receptor signaling pathways. In addition, ATF3 binds to as many as 40% of the p53 targets and preferentially enhances MMS-induced activation of proapoptotic genes such as DR4, DR5, and PUMA, consistent with the proapoptotic effect of ATF3. These data shed new light on the co-regulatory function of ATF3 in the stress-induced transcription factor network. The comprehensive list of genomic targets of ATF3 will facilitate further understanding the role of ATF3 in determining life and death of cells under both physiological and tumour-associated stress conditions. Maintenance of genetic integrity is fundamental to survival of all organisms. DNA damage can be caused by various agents in environment and elicits complex responses in the cell. ATF3 is one of the transcription factors activated by various stress conditions including DNA damage, and has been shown to have pleiotropic effects on life and death of cells depending on the context of experimental conditions. It has been largely unknown, however, which genes and pathways are regulated by stress-induced ATF3. Here we attempted to answer this question by chromatin immunoprecipitation-microarray analysis of downstream targets of ATF3. We show that ATF3 binds to an unexpectedly large number of promoters (nearly 6,000) in a human colorectal cancer cell lineHCT116 treated with an alkylating agent methyl methanesulfonate. Interestingly, the ATF3 targets are highly enriched for binding sites of other stress sensors shedding light on a transcriptional co-regulatory network of DNA damage response. We further show that ATF3 regulates expression of genes in select biological processes including cell cycle, cell death, adhesion, metabolism, signal transduction, and the p53 pathway. The comprehensive list of ATF3 targets provides new insight into a highly inter-connected network of stress-induced transcription factors around ATF3. ChIP-chip samples: Comparison of ATF3-IP and whole genome DNA (control) Gene expression samples: HCT116 cells pre-transfected with either control siRNA or ATF3 knockdown siRNA and stimulated by methyl methanesulfonate (MMS) for 0, 6, 12, and 24 hours
2010-10-01 | E-GEOD-18457 | biostudies-arrayexpress
Project description:Expression of the activating transcription factor 3 (ATF3) gene is induced by Toll-like receptor (TLR) signaling. In turn, ATF3 protein inhibits the expression of various TLR-driven pro-inflammatory genes. Given its counter-regulatory role in diverse innate immune responses, we defined the effects of ATF3 on neutrophilic airway inflammation in mice. ATF3 deletion was associated with increased lipopolysaccharide (LPS)-driven airway epithelia production of CXCL1, but not CXCL2, findings concordant with a consensus ATF3-binding site identified solely in the Cxcl1 promoter. Unexpectedly, ATF3-deficient mice did not exhibit increased airway neutrophilia after LPS challenge. Bone marrow chimeras revealed a specific reduction in ATF3-/- neutrophil recruitment to wild type lungs. In vitro, ATF3-/- neutrophils exhibited a profound chemotaxis defect. Global gene expression analysis identified ablated Tiam2 expression in ATF3-/- neutrophils. TIAM2 regulates cellular motility by activating Rac1-mediated focal adhesion disassembly. Notably, ATF3-/- and ATF3-sufficient TIAM2 knockdown neutrophils, both lacking TIAM2, exhibited increased focal complex area, along with excessive CD11b-mediated F-actin polymerization. Together, our data describe a dichotomous role for ATF3-mediated regulation of neutrophilic responses: inhibition of neutrophil chemokine production, but promotion of neutrophil chemotaxis. Ly6G+ neutrophils were purified by magnetic beads from WT or ATF3 KO bone marrow and RNA was immediately isolated for global gene expression using microarrays.
2014-04-05 | E-GEOD-53973 | biostudies-arrayexpress
Project description:To investigate the dependency on gene expression on the PRR-activated transcription factor IRF3 versus the type I IFN receptor (IFNAR)-activated transcription factor ISGF3, we extracted primary murine embryonic fibroblasts (MEF) of wild-type, IRF3-knockout or IFNAR-knockout mice (strain C57BL/6J, protocol of Podlech et al., 2002). We stimulated the 3 different cell lines by transfection of immunostimulatory DNA (ISD, 4 hours) for activation of IRF3, or by treatment with murine IFNbeta (3 hours) for activation of the IFNAR-ISGF3 cascade. Mock-transfected (4 hours) or untreated cells served as respective controls. In the last 2 hours before harvest, cells were additionally treated with 200µM 4-thiouridine (4sU) for metabolic labelling of nascent transcripts, and total mRNAs were processed accordingly by SLAM-sequencing procedures for gene expression profiling of newly synthesized transcripts.
2023-05-08 | GSE224855 | GEO
Project description:Type I Interferons (IFN-I) are anti-viral and immuno-modulating cytokines involved in many steps across tumor initiation and progression. IFN-I act directly on tumor cells inhibiting cell growth and indirectly by activating immune cells to mount antitumor response. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in Her2/neu transgenic (neuT) mice carrying a non-functional mutation in the IFN-I receptor (IFNAR1), thus being unresponsive to this family of cytokines. Compared to parental neu+/-mice (neuT mice), IFNAR1-/- neu+/- mice (IFNAR-neuT mice) showed earlier onset and increased tumor multiplicity with marked vascularization. Of note, IFNAR-neuT tumors specifically exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including breast cancer stem cells (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1). An increased amount of BCSC was observed in IFNAR-neuT tumors, as assessed by ALDH1A1 enzymatic activity, clonogenic assay and tumorigenic capacity. In vitro exposure of neuT+ mammospheres and cell lines to anti-IFN-I antibodies resulted in increased frequency of ALDH+ cells, suggesting that IFN-I control stemness in tumor cells. Altogether, these results reveal an essential role of IFN-I in NeuT-driven spontaneous carcinogenesis through intrinsic control of BCSC.
2018-05-22 | GSE110350 | GEO