Perturbational sequencing of patient tumors reveals midkine as an innate immune checkpoint in neuroendocrine tumors
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina NovaSeq X
ORGANISM(S): Homo sapiens
SUBMITTER: Jeffrey Ishizuka
PROVIDER: E-MTAB-15926 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Single-cell RNA-seq of human dermal fibroblasts, stimulated with IFNB 1000 IU for 2 or 6 hours, and profiled using the SmartSeq2 protocol.
2018-07-16 | E-MTAB-7051 | biostudies-arrayexpress
Project description:Parkinson disease (PD) is a neurodegenerative disease believed to initiate in the brainstem and then spread throughout the brain. The mechanism by which this occurs is not yet fully understood, but here we show that damaged mitochondrial DNA (mtDNA) plays an important role in this process, which can be initiated by dysregulation of the IFNb/IFNAR signalling pathway. We report that lack of neuronal IFNb/IFNAR, which is associated to the development of PD, causes oxidization, mutation, and deletion in mtDNA. Damaged mtDNA is subsequently extruded extracellularly and can induce PD symptoms like motor and cognitive impairments in healthy mouse brains. It even leads to neurodegeneration in brain regions far from the injection site, suggesting that damaged mtDNA triggers the propagation of PD hallmarks through the brain. We further show that the mechanism by which damaged mtDNA causes pathology in healthy neurons is independent of cGAS and IFNb/IFNAR, but it is mediated by activation of dual Toll-like receptor (TLR)4/9 pathways. Through a proteomic analysis of extracellular vesicles containing the damaged mtDNA, we identified the TLR4 activator Ribosomal Protein S3 (Rps3) and established that Rps3 is a key effector protein involved in damaged mtDNA extrusion and recognition. Collectively, these results reveal a new molecular pathway by which damaged mtDNA can initiate and propagate Parkinson's Disease, paving the way for potential new therapies or disease monitoring.
2023-09-18 | PXD038362 | Pride
Project description:The goal of the experiment is to compare the gene expression from LAMP2A-KO xenografts with control tumors.
2025-01-23 | E-MTAB-14665 | biostudies-arrayexpress
Project description:The specific binding of transcription factors to cognate sequence elements is thought to be critical for the generation of specific gene expression programs. The transcription factors nuclear factor kB (NF-kB) and the interferon (IFN) regulatory factors (IRFs) bind to the kB site and the interferon response element (IRE), respectively, of target genes, and they are activated in macrophages after exposure to pathogens. However, how these factors produce pathogen-specific inflammatory and immune responses remains poorly understood. Combining top-down and bottom-up systems biology approaches, we have identified the NF-kB p50 homodimer (p50:p50) as a regulator of IRF responses. First, unbiased genome-wide expression analysis revealed that p50 repressed a subset of IFN-inducible genes through a previously uncharacterized subclass of guanine-rich IRE (G-IRE) sequences, which was substantiated by biochemical and structural analyses. Second, mathematical modeling predicted that p50:p50 might enforce the stimulus-specificity of composite promoters. Indeed, the production of the antiviral regulator IFN-b was rendered stimulus-specific by the binding of p50:p50 to the G-IRE–containing IFNb enhancer to suppress cytotoxic IFN signaling. Specifically, a deficiency in p50 resulted in the inappropriate production of IFN-b in response to bacterial DNA sensed by Toll-like receptor 9. This role for NF-kB p50 in enforcing the specificity of the cellular response to pathogens by binding to a previously uncharacterized subset of IRE sequences alters our understanding of how the NF-kB and IRF signaling systems cooperate to regulate antimicrobial immunity. [BMDM]: Total RNA extracted from wt, p50-/- or ifnar-/- bone marrow derived macrophages (BMDMs) were subjected to stimulation with LPS, CpG or IFNb [MEF]: Total RNA extracted from wt or p50KO primary mouse embryonic fibroblasts were subjected to stimulation with LPS or IFNb
2011-03-01 | E-GEOD-27112 | biostudies-arrayexpress
Project description:IFNb has been used as a first line therapy for relapsing remitting multiple sclerosis (RRMS). Since only a few studies have addressed the role of endogenous IFNb in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In-vitro studies have demonstrated that IFNb inhibited IL-17A, IL-17F, IL-21, IL-22 and IFN-b secretion in CD4+ lymphocytes through the induction of suppressor of cytokine secretion (SOCS)1 and 3. We found that patients with RRMS have increased serum and cerebrospinal fluid (CSF) Th17 (IL-17A and IL-17F) cytokine levels in comparison to the control subjects, suggesting that deficient endogenous IFNbeta secretion and/or signaling may contribute to the dysregulation of those pathogenic cytokines in CD4+ cells. We identified that the endogenous IFNb from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison to healthy controls (HCs). In addition, in-vitro studies have revealed a deficient endogenous and exogenous IFNb signaling in CD4+ cells derived from MS patients. Interestingly, upon inhibition of the endogenous IFNb signaling by silencing interferon regulatory factor (IRF)7 gene expression, the resting CD4+ T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22 and IL-9, suggesting that endogenous IFNb suppresses the secretion of these pathogenic cytokines. In-vivo recombinant IFNb-1a treatment induced IFNAR1 and its downstream signaling moleculesM-bM-^@M-^Y gene expression, suggesting that treatment may reconstitute a deficient endogenous IFNbeta regulation of the CD4+ T-cellsM-bM-^@M-^Y pathogenic cytokine production in MS patients. Gene expression changes induced by IFNM-NM-2M-bM-^HM-^R1a were tested using Affymetrix Human Genome U133 (HG-U133) arrays (Affymetrix) that contain 45,000 probe sets representing 39,000 transcripts derived from approximately 33,000 human genes. 107 PBMCs per condition derived from 15 CIS patients were stimulated with plate-immobilized M-NM-1CD3 (1 M-NM-<g/ml) and M-NM-1CD28 (5 M-NM-<g/ml) mAb (BD Biosciences) in the absence or presence of IFNM-NM-2-1a (1000 U/ml) (EMD Serono Inc) for 24 h in serum-free medium (Gibco). Cells were harvested and the total RNA was isolated using a Rneasy kit (Quiagen). Arrays were hybridized for 16 hours at 45oC in the GeneChipM-BM-. Hybridization Oven 640 (Affymetrix). The arrays were washed and stained with R-phycoerythrin streptavidin in the GeneChipM-BM-. Fluidics Station 400 (Affymetrix). The arrays were scanned with a Hewlett Packard GeneArray Scanner. Affymetrix GeneChipM-BM-. Microarray Suite 5.0 software was used for washing, scanning and basic analysis.
2014-05-15 | E-GEOD-53716 | biostudies-arrayexpress
Project description:Variation in individuals' adaptive immune response is believed to influence susceptibility to complex diseases in humans. The genetic basis of such variation is poorly understood. We measured gene expression from resting and activated CD4+ T cells derived from the peripheral blood of healthy individuals. We activated the primary T cells with anti-CD3/CD28 beads alone or with IFNb or Th17 polarizing cytokines. We collected peripheral blood from each human donor. We isolated peripheral blood mononuclear cells by Ficoll, and negatively selected for CD4+ T cells using RosettaSep. We then either left cells unstimulated or stimulated them with beads conjugated with anti-CD3 and anti-CD28 either without additional cytokines, or with IFNb, or with Th17 cocktail. Cells were harvest at up to 8 time points (0hr, 45min, 2hr, 4hr, 10hr, 24hr, 48hr and 72hr), lysed and RNA isolated to be profiled on microarray.
2014-08-28 | E-GEOD-60234 | biostudies-arrayexpress
Project description:A number of IFN-induced proteins are believed to be responsible for the antiviral state induced by IFNs. Our microarray analysis of IFN-regulated genes in MEFs from wild-type mice identified 124 probe sets that were differentially regulated upon IFN treatment. This group consisted of many known ISGs such as Ifit1, Gbp2, mx1, Isg15, Stat1, nmi, mx2, If204, Adar, Irf1, and protein kinase R. Experiment Overall Design: 3 control and 3 IFNb-treated biological replicates were analyzed.
2007-10-12 | E-GEOD-3400 | biostudies-arrayexpress
Project description:Dermal fibroblasts from human, rhesus macaque, mouse and rat, stimulated with dsRNA (poly I:C), interferon and controls.<br>The innate immune response - the expression programme that is initiated once a pathogen is sensed - is known to be variable among responding cells, as well as to rapidly evolve in the course of mammal evolution. To study the transcriptional divergence and cell-to-cell variability of this response, we stimulated dermal fibroblast cells from two primates (human and macaque) and two rodents (mouse and rat) with dsRNA - a mimic of viral RNA that elicits a rapid innate immune response. Subsequently, we profiled the response using bulk RNA-seq, scRNA-seq and ChIP-seq across the four species and across different time points.
2018-07-06 | E-MTAB-5919 | biostudies-arrayexpress
Project description:Human brain development is a complex process involving neural proliferation, differentiation, and migration which are directed by many essential cellular factors and drivers. Here, using the NetBID2 algorithm and developing human brain RNA sequencing(RNA-Seq) dataset, we identified synaptotagmin-like 3(SYTL3) as one of the top drivers of early human brain development. Interestingly, SYTL3 exhibited high activity but low expression in both early developmental human cortex and human embryonic stem cell(hESC)-derived neurons. Knockout of SYTL3(SYTL3 -KO) in human neurons or knockdown of Sytl3 in embryonic mouse cortex markedly promoted neuronal migration. Besides, SYTL3-KO caused an abnormal distribution of deep-layer neurons in brain organoids and reduced presynaptic neurotransmitter release in hESC-derived neurons. We further demonstrated that SYTL3-KO- accelerated neuronal migration was modulated by high expression of matrix metalloproteinases. Together, based on bioinformatics and biological experiments, we identified SYTL3 as a novel regulator of cortical neuronal migration in human and mouse developing brains.
2021-02-07 | E-MTAB-10058 | biostudies-arrayexpress
Project description:Using ChIP-Seq analysis we define genes induced in macrophages through synergistic transcriptional activation by NFkB and the IFNb-activated transcription factor ISGF3.
2015-06-15 | E-MTAB-2972 | biostudies-arrayexpress