Transcriptome analysis of differentially expressed genes by tryptophanyl-tRNA synthetase 1 in human peripheral blood mononuclear cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE243125 | GEO | 2023/09/22
REPOSITORIES: GEO
Similar Datasets
Project description:An orthogonal aminoacyl-tRNA synthetase/tRNA pair is a key prerequisite for site-specific incorporation of unnatural amino acids. Due to its high codon suppression efficiency and full orthogonality, the pyrrolysyl-tRNA synthetase/pyrrolysyl-tRNA pair is currently the ideal system for genetic code expansion in both eukaryotes and prokaryotes. There is a pressing need to discover or engineer other fully orthogonal translation systems that allow unnatural amino acids with distinct scaffolds and functionalities to be incorporated into a wide range of living organisms efficiently. Here, through rational chimera design by transplanting the key orthogonal components from the pyrrolysine system, we create multiple chimeric tRNA synthetase/chimeric tRNA pairs, including chimera histidine, phenylalanine, and alanine systems. We further show that these engineered chimeric systems are orthogonal and highly efficient with comparable flexibility to the pyrrolysine system. In addition, the chimera phenylalanine system can incorporate a group of phenylalanine, tyrosine and tryptophan analogues efficiently in both E. coli and mammalian cells. These aromatic amino acids analogous exhibit unique properties and characteristics, including fluorescence, post-translation modification. To our knowledge, most of these molecules have never been shown to be incorporated with fully orthogonal pairs. Therefore, these chimera pairs offer the potential for incorporation of de novo unnatural amino acids into target proteins for a variety of applications.
2020-05-25 | PXD018660 | Pride
Project description:Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, genetically heterogeneous autosomal recessive immune disorder that results when the critical regulatory pathways that mediate immune defense mechanisms and the natural termination of immune/inflammatory responses are disrupted or overwhelmed. In order to advance the understanding of FHL, we performed gene expression profiling of peripheral blood mononuclear cells (PBMCs) from 11 children with untreated FHL. Total RNA was isolated and gene expression levels were determined using microarray analysis. Comparisons between patients with FHL and normal pediatric controls (n = 30) identified 915 down-regulated and 550 up-regulated genes with 2.5-fold difference in expression (P = 0.05). The expression of genes associated with natural killer cell functions, innate and adaptive immune responses, pro-apoptotic proteins, and B- and T-cell differentiation were down-regulated in patients with FHL. Genes associated with the canonical pathways of IL-6, IL-10 IL-1, IL-8, TREM1, LXR/RXR activation, and PPAR signaling and genes encoding of anti-apoptotic proteins were overexpressed in patients with FHL. This, first study of genome-wide expression profiling in children with FHL demonstrates the complexity of gene expression patterns, which underly the immunobiology of FHL. 11 Patients and 33 controls
2011-12-12 | E-GEOD-26050 | biostudies-arrayexpress
Project description:Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model we identify alterations in tryptophan metabolism, and specifically indole, that correlate with disease. We demonstrate that both bacteria and dietary tryptophan are required for disease, and indole supplementation is sufficient to induce disease in their absence. When mice with CIA on a low-tryptophan diet were supplemented with indole, we observed significant increases in serum IL-6, TNF, and IL-1β; splenic RORγt+CD4+ T cells and ex vivo collagen-stimulated IL-17 production; and a pattern of anti-collagen antibody isotype switching and glycosylation that corresponded with increased complement fixation. IL-23 neutralization reduced disease severity in indole-induced CIA. Finally, exposure of human colon lymphocytes to indole increased expression of genes involved in IL-17 signaling and plasma cell activation. Altogether, we propose a mechanism by which intestinal dysbiosis during inflammatory arthritis results in altered tryptophan catabolism, leading to indole stimulation of arthritis development. Blockade of indole generation may present a novel therapeutic pathway for RA and SpA.
2023-11-13 | GSE241655 | GEO
Project description:Even though cancer patients are generally considered more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the mechanisms driving their predisposition to severe forms of coronavirus disease 2019 (COVID-19) have not yet been deciphered. Since metabolic disorders are associated with homeostatic frailty, which increases the risk of infection and cancer, we asked whether we could identify immunometabolic pathways intersecting with cancer and SARS-CoV-2 infection. Thanks to a combined flow cytometry and multiomics approach, here we show that the immunometabolic traits of COVID-19 cancer patients encompass alterations in the frequency and activation status of circulating myeloid and lymphoid subsets, and that these changes are associated with i) depletion of tryptophan and its related neuromediator tryptamine, ii) accumulation of immunosuppressive tryptophan metabolites (i.e., kynurenines), and iii) low nicotinamide adenine dinucleotide (NAD+) availability. This metabolic imbalance is accompanied by altered expression of inflammatory cytokines in peripheral blood mononuclear cells (PBMCs), with a distinctive downregulation of IL-6 and upregulation of IFNg mRNA expression levels. Altogether, our findings indicate that cancer not only attenuates the inflammatory state in COVID-19 patients but also contributes to weakening their precarious metabolic state by interfering with NAD+ dependent immune homeostasis.
2023-03-27 | PXD040683 | Pride
Project description:Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early-onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics including fevers and ulcers that responded to IL-1, TNF, or IL-12p40 blockade. Using cells from patients and two newly generated mouse models, we uncovered hyperinflammatory responses of ELF4-mutant macrophages to a range of innate stimuli. Mechanistically, Elf4 in macrophages both sustained expression of anti-inflammatory genes such as Il1rn and limited upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1, and neutrophil chemoattractants. Indeed, therapeutic Trem1 blockade reversed inflammation and intestine pathology in Elf4-mutant mice challenged with lipopolysaccharide in vivo. Thus, the ELF4 transcription factor restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory diseases such as IBD.
2021-07-29 | GSE175569 | GEO
Project description:AKT signaling pathway plays critical roles in the resolution of inflammation. However, the underlying mechanisms of anti-inflammatory regulation and signal coordination remain unclear. Here, we report that anti-inflammatory AKT signaling is coordinated by glutamyl-prolyl-tRNA synthetase 1 (EPRS1). Upon inflammatory activation, AKT specifically phosphorylated Ser999 of EPRS1 in the cytoplasmic multi-tRNA synthetase complex, inducing release of EPRS1. The EPRS1 compartmentalized AKT to early endosomes via selective binding to the endosomal membrane lipid phosphatidylinositol 3-phosphate and assembled an AKT signaling complex specific for anti-inflammatory activity. These events promoted AKT activation-mediated GSK3β phosphorylation, which increased anti-inflammatory cytokine production. EPRS1-deficient macrophages could not assemble the early endosomal complex and consequently exacerbated inflammation, decreasing the survival of EPRS1-deficient mice undergoing septic shock and ulcerative colitis. Collectively, our findings show that the housekeeping protein EPRS1 acts as a mediator of inflammatory homeostasis by coordinating compartment-specific AKT signaling
2022-10-12 | PXD036072 | Pride
Project description:RNA ligation can regulate RNA function by altering RNA sequence, structure and coding potential. For example, the function of XBP1 in mediating the unfolded protein response requires RNA ligation, as does the maturation of some tRNAs. Here, we describe a novel in vivo model in C. elegans for the conserved RNA ligase RtcB, and show that RtcB ligates the xbp 1 mRNA during the IRE 1 branch of the unfolded protein response. Without RtcB, protein stress results in the accumulation of unligated xbp-1 mRNA fragments, defects in the unfolded protein response, and decreased lifespan. RtcB also ligates endogenous pre tRNA halves, and RtcB mutants have defects in growth and lifespan that can be bypassed by expression of pre-spliced tRNAs. In addition, animals that lack RtcB have defects that are independent of tRNA maturation and the unfolded protein response. Thus, RNA ligation by RtcB is required for the function of multiple endogenous target RNAs including both xbp-1 and tRNAs. RtcB is uniquely capable of performing these ligation functions, and RNA ligation by RtcB mediates multiple essential processes in vivo. 4 paired-end RNA-seq reads. Control worms have pre-spliced tRNAs, RtcB-null have mutated RtcB, +/- tunicamycin treatment
2014-09-24 | E-GEOD-61733 | biostudies-arrayexpress
Project description:Chronic stress contributes to the development of psychiatric disorders including anxiety and depression. Several inflammatory-related effects of stress are associated with increased interleukin-1 (IL-1) signaling within the central nervous system and are mediated by IL-1 receptor 1 (IL-1R1) on several distinct cell types. Neuronal IL-1R1 is prominently expressed on the neurons of the dentate gyrus, but its role in mediating behavioral responses to stress is unknown. We hypothesize that IL-1 acts on this subset of hippocampal neurons to influence cognitive and mood alterations with stress. Here, mice subjected to psychosocial stress showed reduced social interaction and impaired working memory, and these deficits were prevented by global IL-1R1 knockout. Selective deletion of IL-1R1 in glutamatergic neurons (nIL-1R1-/-), abundant in the hippocampus wherein the inflammatory-influenced effects were observed, abrogated the stress-induced deficits in social interaction and working memory. RNA-sequencing of microdissected hippocampi revealed that stress increased several canonical pathways (TREM1, NF-κ, complement, IL-6 signaling) and upstream regulators (INFγ, IL-1β, NF-κB, MYD88) associated with inflammation. The inductions of TREM1 signaling, complement, and leukocyte extravasation with stress were reversed by nIL-1R1-/-. Collectively, we show that stress-dependent IL-1R1 signaling in hippocampal neurons represents a novel mechanism by which inflammation is perpetuated and social interactivity and working memory are modulated.
2020-04-24 | GSE149195 | GEO
Project description:Resistance to erythropoietin (EPO) treatment is observed in a considerable proportion of anemic patients with chronic kidney disease. Previous reports suggest that inflammation is one of the major independent predictors of this resistance, and pro-inflammatory cytokines have been shown to inhibit erythropoiesis. The aim of this study was to investigate EPO-induced modification to gene expression in primary cultured leukocytes. Microarray experiments were performed on ex vivo Peripheral Blood Mononuclear Cells (PBMCs) from pooled ten healthy donors (n=9), primed or not with TNF-alpha, and treated with recombinant human erythropoietin alpha (EPO-alpha). Real-time PCR experiments were used to validate expression of the molecular targets considered most relevant for inflammation. Data analysis suggested that EPO-alpha treatment mainly modulated genes involved in cell movement and cell-cell interaction in primed PBMCs. Notably, EPO-alpha exerts anti-inflammatory effects inhibiting the expression of pro-inflammatory cytokine IL-8 and its receptor CXCR2; by contrast, EPO-alpha further increases expression of genes relating to promotion of inflammation encoding for IL-1beta and CCL8, and induces de novo synthesis of IL-1alpha, CXCL1 and CXCL5 in primed PBMCs. MAPK p38alpha?reducing activity is involved in modulation of IL-1beta and IL-8 expression. In conclusion, our findings confirm the anti-inflammatory role for EPO, but also suggest a plausible in vivo scenario, in which the positive correlation found between EPO-resistance and elevated levels of some pro-inflammatory mediators is due to treatment with EPO itself. One future objective will be to perform in vivo measurement of the molecular targets highlighted, in order to identify any additional markers involved in EPO-resistance among hypo-responsive patients. In this study, we analyzed the expression profiles of pooled blood PBMCs from 10 healthy donors primed or not with TNF-alpha and then treated with EPO-alpha. All RNAs from no stimulated PBMCs were hybridized against RNAs from PBMCs treated with TNF-alpha or TNF-alpha and EPO-alpha. We performed a total of 9 technical replicates.
2013-12-19 | E-GEOD-53336 | biostudies-arrayexpress
Project description:Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, genetically heterogeneous autosomal recessive immune disorder that results when the critical regulatory pathways that mediate immune defense mechanisms and the natural termination of immune/inflammatory responses are disrupted or overwhelmed. In order to advance the understanding of FHL, we performed gene expression profiling of peripheral blood mononuclear cells (PBMCs) from 11 children with untreated FHL. Total RNA was isolated and gene expression levels were determined using microarray analysis. Comparisons between patients with FHL and normal pediatric controls (n = 30) identified 915 down-regulated and 550 up-regulated genes with 2.5-fold difference in expression (P = 0.05). The expression of genes associated with natural killer cell functions, innate and adaptive immune responses, pro-apoptotic proteins, and B- and T-cell differentiation were down-regulated in patients with FHL. Genes associated with the canonical pathways of IL-6, IL-10 IL-1, IL-8, TREM1, LXR/RXR activation, and PPAR signaling and genes encoding of anti-apoptotic proteins were overexpressed in patients with FHL. This, first study of genome-wide expression profiling in children with FHL demonstrates the complexity of gene expression patterns, which underly the immunobiology of FHL.
2011-12-12 | GSE26050 | GEO