Ontology highlight
ABSTRACT:
PROVIDER: PRJNA933282 | ENA |
REPOSITORIES: ENA
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Project description:Despite their enormous importance, the molecular circuits that control the differentiation of Th17 cells remain largely unknown. Recent studies have reconstructed regulatory networks in mammalian cells, but have focused on short-term responses and relied on perturbation approaches that cannot be applied to primary T cells. Here, we develop a systematic strategy – combining transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowire-based tools for performing gene perturbations in primary T cells – to derive and experimentally validate a temporal model of the dynamic regulatory network that controls Th17 differentiation. The network is arranged into two self-reinforcing and mutually antagonistic modules that either suppress or promote Th17 differentiation. The two modules contain 12 novel regulators with no previous implication in Th17 differentiation, which may be essential to maintain the appropriate balance of Th17 and other CD4+ T cell subsets. Overall, our study identifies and validates 39 regulatory factors that are embedded within a comprehensive temporal network and identifies novel drug targets and organizational principles for the differentiation of Th17 cells. DNA binding of TSC22D3 in Th17 cells compared to WCE
2013-03-07 | E-GEOD-43949 | biostudies-arrayexpress
Project description:The early stages of human Th17 Cell differentiation were studied using label free proteomics to compare Th17 polarized CD4+ human T cells at 24 h and 72 h with activated cells (72 and 24 h) and Thp cells.
2019-01-28 | PXD008973 | Pride
Project description:The Kaposiâs Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposiâs Sarcoma (KS), which preferentially arise in immunocompromised patients but lack of effective therapeutic options. We have previously shown that KSHV or viral protein LANA can upregulate the glycoprotein CD147 (Emmprin) to induce primary endothelial cell invasiveness, which also requires PI3K/Akt and MAPK activation of VEGF production. In the current study, we first time identify the global network controlled by CD147 in KSHV-infected endothelial cells using Illumina microarray analysis. Among these downstream genes, ADAMTS1 and 9, two specific metalloproteases are strongly expressed in AIDS-KS tissues and contributed to KSHV-infected cell invasiveness through regulation of related cytokines production and respective receptors expression. By using a nude mice KS-like model, we found that targeting CD147 and downstream ADAMTSs proteins significantly suppressed KSHV-related tumorigenesis in vivo, which is potentially through impairing extracellular matrix (ECM) formation in tumor microenvironment. Taken together, we think that targeting CD147 and related proteins may represent a promising therapeutic strategy against KSHV-related malignancies. HUVEC cells were infected by KSHV or transduced by a CD147 recombinant adenoviral vector and the gene expression signature was compared to respective controls
2016-05-31 | E-GEOD-69067 | biostudies-arrayexpress
Project description:CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity. Crucial for T helper17 (Th17) cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification. Herein, we show that Th17 differentiation occurs in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 in the absence of TGF-β1 were more pathogenic in this experimental disease. These data suggest a new model for Th17 differentiation. Consistent with genetic data linking the IL23R with autoimmunity, our findings re-emphasize the role of IL-23 and therefore have important implications for the development of new therapies. Examination of Stat3 binding and H3K4me and H3Ac in helper T cells.
2010-08-31 | E-GEOD-23681 | biostudies-arrayexpress
Project description:T helper (Th) cells control host defense to pathogens. IL 12R expression is required for Th1, IL-4RM-NM-1 for Th2, and IL-6RM-NM-1/gp130 for Th17 differentiation to allow responsiveness to IL-12, IL-4, and IL-6, respectively. IL-2 via STAT5 controls Th2 differentiation by regulating the Th2 cytokine gene cluster and Il4ra expression. Here we show that IL-2 regulates Th1 differentiation, inducing STAT5-dependent IL-12RM-NM-22 and T-bet expression, with impaired human Th1 differentiation when IL-2 was blocked. Th1 differentiation was also impaired in mouse Il2-/- T cells but restored by IL-12RM-NM-22 expression. Consistent with IL-2M-bM-^@M-^Ys inhibition of Th17 differentiation, IL-2 decreased Il6ra and Il6st/gp130 expression, and Il6st augmented Th17 differentiation even when IL-2 was present. Thus, IL-2 influences T-cell differentiation by modulating cytokine receptor expression to help specify/maintain differentiated states. Genome-wide mapping of STAT1,STAT4,STAT5A,STAT5B binding to their target genes in Th1 or human CD4+ cells was conducted
2011-04-24 | E-GEOD-27158 | biostudies-arrayexpress
Project description:The Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s Sarcoma (KS), which preferentially arise in immunocompromised patients but lack of effective therapeutic options. We have previously shown that KSHV or viral protein LANA can upregulate the glycoprotein CD147 (Emmprin) to induce primary endothelial cell invasiveness, which also requires PI3K/Akt and MAPK activation of VEGF production. In the current study, we first time identify the global network controlled by CD147 in KSHV-infected endothelial cells using Illumina microarray analysis. Among these downstream genes, ADAMTS1 and 9, two specific metalloproteases are strongly expressed in AIDS-KS tissues and contributed to KSHV-infected cell invasiveness through regulation of related cytokines production and respective receptors expression. By using a nude mice KS-like model, we found that targeting CD147 and downstream ADAMTSs proteins significantly suppressed KSHV-related tumorigenesis in vivo, which is potentially through impairing extracellular matrix (ECM) formation in tumor microenvironment. Taken together, we think that targeting CD147 and related proteins may represent a promising therapeutic strategy against KSHV-related malignancies.
2016-05-31 | GSE69067 | GEO
Project description:Smad4 was required for febrile temperature enhanced Th17 differentiation. In order to further understand the mechanisms whereby Smad4 enhance Th17 differentiation, we conducted ChIP-seq analysis of Smad4 in Th17 cells cutured 37°C and 39.5°C after 24 hours.
2020-06-26 | GSE125263 | GEO
Project description:T helper 17 (Th17) cells are a distinct subset of CD4+ T cells necessary for maintaining gut homeostasis and have prominent roles in autoimmunity and inflammation. Th17 cells have unique metabolic features, including a stem cell-like signature and reliance on mitochondrial respiratory chain function and tricarboxylic acid (TCA) cycle to coordinate metabolic and epigenetic remodeling. Dynamic changes in mitochondrial membrane morphology are key to sustain organelle function. However, it remains unclear whether mitochondrial membrane remodeling orchestrates metabolic and differentiation events in Th17 cells. Here we demonstrate that mitochondrial membrane fusion and tight cristae organization are required for Th17 cell function (i.e. cytokine expression). As a genetic model system we employ Th17 specific deletion of optic atrophy 1 (OPA1), a gene that encodes a protein involved in mitochondrial inner membrane fusion and cristae organization. As a result, we find that Th17 cells rely on mitochondrial fusion (due to their low metabolic activity). Here, we carry out DIA-based differential quantitative proteomic analysis of murine wild-type and OPA1 knock-out Th17 cells. Through Ingenuity pathway analysis and together with transcriptional and metabolomic profiling we identify the serine/threonine kinase liver associated kinase B1 (LKB1/STK11) as an essential node coupling mitochondrial function to IL-17A cytokine expression in T cells.
2022-10-13 | PXD036162 | Pride
Project description:T helper 17 (Th17) cells protect against fungal and bacterial infections and are implicated in autoimmunity. Several long intergenic noncoding RNAs (lincRNA) are induced during Th17 differentiation, however, their contribution to Th17 differentiation is poorly understood. We discovered a lincRNA myocardial infarction associated transcript (MIAT) to be upregulated early after induction of human Th17 cell differentiation along with an increase in the chromatin accessibility at the gene locus. We found that MIAT deficiency leads to chromatin accessibility at several loci including IL17A promoter.
2022-05-25 | GSE183918 | GEO
Project description:Fusobacterium nucleatum can bind to host cells and potentiate intestinal tumorigenesis. Here, we used a genome-wide screen to identify an adhesin, RadD, which facilitates the attachment of F. nucleatum to CRC cells in vitro. RadD directly binds to CD147, a receptor overexpressed on CRC cell surfaces, which initiated a PI3K-AKT-NF-κB-MMP9 cascade, subsequently enhancing tumorigenesis in mice. Clinical specimen analysis showed that elevated radD gene levels in CRC tissues correlated positively with activated oncogenic signaling and poor patient outcomes. Finally, blockade of the interaction between RadD and CD147 in mice effectively impaired F. nucleatum attachment and attenuated F. nucleatum-induced oncogenic response. Together, our study provides insights into an oncogenic mechanism driven by F. nucleatum RadD and suggests that the RadD-CD147 interaction could be a potential therapeutic target for CRC.
2024-06-11 | GSE245617 | GEO