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The Type I interferon response impairs differentiation potential of pluripotent stem cells [RT-qPCR]

ABSTRACT: Upon virus infection,pluripotent stem cells neither induce nor respond to canonical Type I interferons (IFN-I). To better understand this biology,we characterized induced pluripotent stem cells (iPSCs) as well as their differentiated parental or re-derived counterparts. We confirmed that only iPSCs failed to respond to viral RNA,Type I interferon (IFN-I),or viral infection. This lack of response could be phenocopied in fibroblasts with the expression of a reprogramming factor which repressed the capacity to induce canonical antiviral pathways. To ascertain the consequences of restoring the antiviral response in the context of pluripotency,we engineered a system to engage these defenses in iPSCs. Inducible expression of a recombinant virus-activated transcription factor resulted in the successful reconstitution of antiviral defenses through the direct upregulation of IFN-I stimulated genes. Induction of the antiviral signature in iPSCs,even for a short duration,resulted in the dysregulation of genes associated with all three germ layers despite maintaining pluripotency markers. Trilineage differentiation of these same cells showed that engagement of the antiviral defenses compromised ectoderm and endoderm formation and dysregulated the development of mesodermal sublineages. In all,these data suggest that the temporal induction of the antiviral response primes iPSCs away from pluripotency and induces numerous aberrant gene products upon differentiaton. Together these results suggest that the IFN-I system and pluripotency may be incompatible with each other and thus explain why stem cells do not utilize the canonical antiviral system.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122793 | GEO | 2018/11/22

REPOSITORIES: GEO

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The Type I interferon response impairs differentiation potential of pluripotent stem cells [seq]

Project description:Upon virus infection,pluripotent stem cells neither induce nor respond to canonical Type I interferons (IFN-I). To better understand this biology,we characterized induced pluripotent stem cells (iPSCs) as well as their differentiated parental or re-derived counterparts. We confirmed that only iPSCs failed to respond to viral RNA,Type I interferon (IFN-I),or viral infection. This lack of response could be phenocopied in fibroblasts with the expression of a reprogramming factor which repressed the capacity to induce canonical antiviral pathways. To ascertain the consequences of restoring the antiviral response in the context of pluripotency,we engineered a system to engage these defenses in iPSCs. Inducible expression of a recombinant virus-activated transcription factor resulted in the successful reconstitution of antiviral defenses through the direct upregulation of IFN-I stimulated genes. Induction of the antiviral signature in iPSCs,even for a short duration,resulted in the dysregulation of genes associated with all three germ layers despite maintaining pluripotency markers. Trilineage differentiation of these same cells showed that engagement of the antiviral defenses compromised ectoderm and endoderm formation and dysregulated the development of mesodermal sublineages. In all,these data suggest that the temporal induction of the antiviral response primes iPSCs away from pluripotency and induces numerous aberrant gene products upon differentiaton. Together these results suggest that the IFN-I system and pluripotency may be incompatible with each other and thus explain why stem cells do not utilize the canonical antiviral system.

2018-11-22 | GSE122791 | GEO

Engineered mammalian RNAi can elicit antiviral protection that negates the requirement for the interferon response

Project description:While the intrinsic antiviral cell defenses of many kingdoms utilize pathogen-specific small RNAs, the antiviral response of chordates is primarily protein-based and not uniquely tailored to the incoming microbe. In an effort to explain this evolutionary bifurcation, we determined whether antiviral RNA interference (RNAi) was sufficient to replace the protein-based type I interferon (IFN-I) system of mammals. To this end, we recreated an RNAi-like response in mammals and determined its effectiveness to combat influenza A virus in vivo in the presence and absence of the canonical IFN-I system. Mammalian antiviral RNAi, elicited by either host- or virus-derived small RNAs, effectively attenuated virus and prevented disease independently of the innate immune response. These data find that chordates could have utilized RNAi as their primary antiviral cell defense and suggest that the IFN-I system emerged as a result of natural selection imposed by ancient pathogens.

2015-10-03 | GSE73698 | GEO

Transcriptional response to type I IFN in bat P. alecto cells

Project description:Bats are reservoirs of a number of highly pathogenic human viruses, yet they remain relatively asymptomatic during infection. Whether this viral resistance is due to a unique immune system is unknown. An evolutionarily conserved feature of vertebrate antiviral immunity is the interferon (IFN) response, which triggers cellular defenses through interferon-stimulated gene (ISG) expression. While bats encode an intact IFN system, global ISG expression patterns in bat cells are not well characterized. Here, we used RNA-Seq to assess the transcriptional response to IFNα in cells derived from the bat Pteropus alecto (black flying fox). We show induction of more than 100 transcripts, most of which are canonical ISGs observed in other species. Kinetic gene profiling revealed that P. alecto ISGs fall into two unique temporal subclusters with similar early induction kinetics but distinct late-phase declines. In contrast to bat ISGs, human ISGs generally remained elevated for longer periods following IFN treatment, suggesting host-based differences in gene regulatory mechanisms. Notably, we also identified a small group of non-canonical bat ISGs, including an enzymatically active RNASEL. These studies provide insight into the innate immune response of an important viral reservoir and lay a foundation for studies into the immunological features that may underlie a unique virus-host relationship in bats.

2017-11-28 | GSE102296 | GEO

Membrane-proximal motifs are the primary determinants of signaling strength differences between type I and III interferon receptors

Project description:Interferons (IFNs) play crucial roles in antiviral defenses. Despite utilizing the same JAK-STAT signaling cascade, type I and III IFN receptors produce different magnitudes and dynamics in the phosphorylation of signal transducers and activators of transcription (STATs), gene transcription and antiviral responses. Prior studies have tested the role of ligand binding affinity and receptor expression level on IFN receptor signaling strength; however, the ability of intracellular domains to differentiate type I and III IFN signaling has not been previously examined. Therefore, we engineered synthetic, heterodimeric type I and III IFN receptors that can be stably expressed at similar levels in human cells and respond to the same ligand. Even when controlling for ligand binding and receptor expression, we find that our synthetic type I receptors produce a greater magnitude of STAT phosphorylation and gene expression than the corresponding type III receptors. Furthermore, our results show that short <55 amino acid “box motifs” known to bind JAK1 are sufficient to encode differences between type I and III receptors. Altogether, our work indicates that specific regions within the intracellular domains of IFNAR2 and IFNLR1 encode different downstream signaling strengths that allow type I and III receptors to produce distinct signaling outcomes.

2023-10-11 | GSE218585 | GEO

Chemical inhibition of immune signaling rescues defects during heart development in Down syndrome via regulating canonical Wnt pathway

Project description:Congenital heart defects (CHDs) are very frequent in children with Down syndrome (DS), the genetic condition caused by trisomy of chromosome 21 (T21). However, the mechanisms by which T21 causes susceptibility to CHDs are poorly understood. Here, using a combination of human induced pluripotent stem cell (iPSC)-based model and Dp(16)1Yey/+ (Dp16) a mouse model of DS, we identified downregulation of canonical Wnt signaling that is caused by increased dosage of interferon (IFN) receptors encoded on chromosome 21 (HSA21) as a causative factor of CHDs in DS. We differentiated human iPSCs derived from individuals with DS as well as CHDs (DS/CHD iPSCs), and controls (control iPSCs) into cardiac cells. We observed that T21 upregulates IFN signaling, downregulates the canonical WNT pathway, and impairs cardiac differentiation. Furthermore, genetic and pharmacological normalization of IFN pathways restored canonical WNT signaling and rescued defects during cardiac differentiation of DS/CHD iPSCs. Strikingly, treatment with an inhibitor of Janus kinase, which is activated by IFN receptor engagement normalized the canonical Wnt pathway and ameliorated CHDs in Dp16 embryos. Our findings provide new mechanisms underlying CHDs in DS, ultimately aiding the development of novel therapeutic strategies.

2023-06-28 | GSE217557 | GEO

Kinetics and molecular hallmarks of the acquisition of developmental pluripotency during cellular reprogramming [RNA-Seq]

Project description:The ability of induced pluripotent stem cells (iPSCs) to differentiate into all adult cell types makes them attractive for basic research and regenerative medicine applications, but it remains unknown when and how this hallmark of the pluripotent state is established. Here, we pinpoint the acquisition of developmental pluripotency in a suitable reprogramming system and show that nascent iPSCs abruptly and without extensive maturation period in culture become capable of generating all tissues upon injection into preimplantation embryos. Strikingly, the developmental potential of nascent iPSCs is comparable to or even surpasses that of high-quality established pluripotent cells. Further functional assays as well as genome-wide transcriptional and chromatin analyses suggest that cells acquiring developmental pluripotency exhibit a unique combination of molecular and functional properties that distinguish them from canonical pluripotency states. These include reduced clonal self-renewal potential and the elevated expression of transcriptional regulators of postimplantation development. Our observations close an important gap in our understanding of induced pluripotency and provide an improved roadmap of cellular reprogramming with ramifications for the biomedical use of iPSCs.

2018-01-03 | GSE106332 | GEO

Kinetics and molecular hallmarks of the acquisition of developmental pluripotency during cellular reprogramming [ATAC-Seq]

2018-01-03 | GSE106331 | GEO

The NF-κB transcriptional footprint is essential for SARS-CoV-2 replication

Project description:SARS-CoV-2, the etiological agent of COVID-19, is characterized by a delay in Type I interferon (IFN-I)-mediated antiviral defenses alongside robust cytokine production. Here we investigate the underlying molecular basis for this imbalance and implicate virus-mediated activation of NF-κB in the absence of other canonical IFN-I-related transcription factors. Epigenetic and single cell transcriptomic analyses show a selective NF-κB signature that was most prominent in infected cells. Disruption of NF-κB signaling through the silencing of the NF-κB transcription factors p65 or p50 resulted in loss of virus replication that was rescued upon reconstitution. These findings could be further corroborated with the use of NF-κB inhibitors, which reduced SARS-CoV-2 replication in vitro. These data suggest that the robust cytokine production in response to SARS-CoV-2, despite a diminished IFN-I response, is the product of a dependency on NF-κB for viral replication.

2021-09-28 | GSE184536 | GEO

Transcriptome analysis from wild type and nHOTAIRM1 knock-out iPSC-derived spinal motor neurons

Project description:In the central nervous system, motor neurons (MNs) are responsible for controlling essential body functions. Long noncoding RNAs have emerged overwhelmingly as gene expression regulators crucial at any step of MN differentiation and function. To uncover the function of the neuronal lncRNA nHOTAIRM1, abundantly expressed in spinal MNs, we generated, analysed and compared RNA-Seq data from wild type (WT) and nHOTAIRM1 knock-out (KO) MNs derived from iPSCs through a differentiaton protocol of 12 days

2023-11-22 | GSE228681 | GEO

Exercise Activates Interferon Immune Response of the Liver via Gpld1 to Enhance Antiviral Innate Immunity

Project description:<p>Healthy behavioral patterns could modulate organ functions to enhance the body’s immunity. However, whether exercise regulates antiviral innate immunity remains elusive. Here, we found that exercise promotes type-I IFN (IFN-I) production in the liver and enhances IFN-I immune activity of the body. Despite the possibility that many exercise-induced factors could regulate IFN-I production, we identified Gpld1 as a crucial molecule and the liver as the major organ to promote IFN-I production after exercise. Exercise largely loses the efficiency to induce IFN-I in Gpld1-/- mice. Further studies demonstrated that exercise-produced 3-hydroxybutanoic acid (3-HB) critically induces Gpld1 expression in the liver. Gpld1 blocks the PP2A-IRF3 interaction and therefore enhances IRF3 activation and IFN-I production, and improves the body’s antiviral ability. This study reveals that the exercise behavior improves antiviral innate immunity by linking the liver metabolism to systemic IFN-I activity, and uncovers an unknown function of liver cells in innate immunity.</p>

2024-04-24 | MTBLS7972 | MetaboLights

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