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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Chemical Inhibition of the ROR?t-dependent Transcriptional Network in Th17 cells [RNA-Seq]

ABSTRACT: ROR?t is a transcription factor required for T helper 17 (Th17) cell development. We identified three ROR?t-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized ROR?t binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and ROR?t-deficient cells. ROR?t is central in a densely interconnected regulatory network, acting both as a direct activator of genes important for Th17 cell differentiation and as a direct repressor of genes from other T-cell lineages. The three inhibitors identified here reversed both of these modes of action, but to varying extents and through distinct mechanisms. Whereas one inhibitor displaced ROR?t from its target-loci, the two more potent inhibitors affected transcription predominantly without removing DNA-binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity. Transcriptional profiling of Th17 cells under chemical perturbations of ROR?t, DMSO, and knockout of ROR?t

ORGANISM(S): Mus musculus

SUBMITTER: Nir Yosef

PROVIDER: E-GEOD-56018 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Chemical Inhibition of the RORγt-dependent Transcriptional Network in Th17 cells [RNA-Seq 2]

Project description:RORγt is a transcription factor required for T helper 17 (Th17) cell development. We identified three RORγt-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized RORγt binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and RORγt-deficient cells. RORγt is central in a densely interconnected regulatory network, acting both as a direct activator of genes important for Th17 cell differentiation and as a direct repressor of genes from other T-cell lineages. The three inhibitors identified here reversed both of these modes of action, but to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target-loci, the two more potent inhibitors affected transcription predominantly without removing DNA-binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity. Transcriptional profiling of Th17 cells under chemical perturbations of RORγt, DMSO, and knockout of RORγt. It includes repeats for all the data in GSE56018, plus one additional condition.

2014-04-17 | E-GEOD-56240 | biostudies-arrayexpress

Single-cell transcriptional profiling of Th17 cells, harvested at peak of disease in EAE from LN [EAE-LN-IL-17A/GFP+]

Project description:Extensive cellular heterogeneity exists within specific immune-cell subtypes classified as a single lineage, but its molecular underpinnings are rarely characterized at a genomic scale. Here, we use single-cell RNA-seq to investigate the molecular mechanisms governing heterogeneity and pathogenicity of Th17 cells isolated from the central nervous system (CNS) and lymph nodes (LN) at the peak of autoimmune encephalomyelitis (EAE) or polarized in vitro under either pathogenic or non-pathogenic differentiation conditions. Computational analysis reveals a spectrum of cellular states in vivo, including a self-renewal state, Th1-like effector/memory states and a dysfunctional/senescent state. Relating these states to in vitro differentiated Th17 cells, unveils genes governing pathogenicity and disease susceptibility. Using knockout mice, we validate four novel genes: Gpr65, Plzp, Toso and Cd5l (in a companion paper). Cellular heterogeneity thus informs Th17 function in autoimmunity, and can identify targets for selective suppression of pathogenic Th17 cells while sparing non-pathogenic tissue-protective ones. Single-cell transcriptional profiling of Th17 cells, harvested at peak of disease in EAE from LN

2015-11-20 | E-GEOD-75108 | biostudies-arrayexpress

Single-cell transcriptional profiling of Th17 cells, harvested at peak of disease in EAE from CNS [EAE-CNS-IL-17A/GFP+]

2015-11-20 | E-GEOD-75107 | biostudies-arrayexpress

Chemical Inhibition of the RORγt-dependent Transcriptional Network in Th17 cells [ChIP-Seq]

Project description:RORγt is a transcription factor required for T helper 17 (Th17) cell development. We identified three RORγt-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized RORγt binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and RORγt-deficient cells. RORγt is central in a densely interconnected regulatory network, acting both as a direct activator of genes important for Th17 cell differentiation and as a direct repressor of genes from other T-cell lineages. The three inhibitors identified here reversed both of these modes of action, but to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target-loci, the two more potent inhibitors affected transcription predominantly without removing DNA-binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity. DNA binding of RORγt in WT Th17 cells and under chemical perturbations of RORγt; Additional data is included for epitope-tagged exogenous RORγt in EL4 cells (a murine lymphoma cell line)

2014-04-17 | E-GEOD-56019 | biostudies-arrayexpress

Enhanced Pathogenicity of Th17 cells Generated in the Absence of Transforming Growth Factor-β Signaling

Project description:CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity1-4. Crucial for T helper17 (Th17) cells in vivo5,6, 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 specification7-10. 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. Mouse T helper 17 cell differentiation with or without TGFB

2010-08-31 | E-GEOD-23505 | biostudies-arrayexpress

Regulation of gene expression by RORgamma in Th17 cells

Project description:We observed significant growth inhibition of melanoma tumor in ROR?-/- mice, suggesting an important role for the T helper 17 cell (TH17) pathway in tumor immunity. Though RORgamma t (ROR?t) plays a critical role in the development of IL-17-secreting Th17 cells, the role of other genes remained an open question. To explore the expression of unknown genes with anti-tumor properties, gene expression analysis was performed. Sorted naïve TH cells (CD4+CD25-CD62Lhigh) from RORc+/+ and RORc-/-mice were differentiated under TH17 polarizing conditions. After 4 days, cells were harvested, RNA was isolated and gene expression analysis was performed.

2013-04-17 | E-GEOD-38704 | biostudies-arrayexpress

Roles of STAT3 and STAT5 in regulation of gene expression under Th17 differentiation

Project description:Interleukin 2 (IL-2), a cytokine linked to human autoimmune diseases, limits IL-17 production. We show that deletion of Stat3 in T cells abrogates IL-17 production and attenuates autoimmunity associated with IL-2 deficiency. While STAT3 induces IL-17 and ROR?t and inhibits Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and ROR?t. We found that STAT3 and STAT5 bound to multiple common sites across the Il17 genetic locus. The induction of STAT5 binding by IL-2 was associated with a reduction in STAT3 binding at these sites and the inhibition of associated active epigenetic marks. Titrating the relative activation of STAT3 and STAT5 modulated TH17 cell specification. Thus, the balance rather than the absolute magnitude of these signals determines the propensity of cells to make a key inflammatory cytokine. The roles of STAT3 and STAT5 in regulation of gene expression under Th17 differentiation was investigated. Affymetrix Mouse Genome 430 2.0 Arrays were used to evaluate global gene expression.

2011-02-09 | E-GEOD-26551 | biostudies-arrayexpress

Gene expression analysis of human CD4+ T cells differentiated into Th17 cells in the presence of high-salt

Project description:Th17 cells are believed to be a critical cell population for driving autoimmune diseases. However, environmental factors that are directly related to the development of Th17 cells are largely unknown. High-salt (NaCl) concentrations enhance Th17 differentiation of human naive CD4+ T cells in vitro. The aim of the study was to analyse the changes in gene expression induced by high-salt conditions during Th17 differentiation. Naive human CD4+ T cells were in vitro differentiated into Th17 cells in the presence or absence of high-salt. We arrayed 2 different donors for each condition (control & high-salt).

2013-03-07 | E-GEOD-42569 | biostudies-arrayexpress

Population transcriptional profiling of in vitro polarized Th17 cells, either sorted for IL17A/GFP+ or unsorted

Project description:Extensive cellular heterogeneity exists within specific immune-cell subtypes classified as a single lineage, but its molecular underpinnings are rarely characterized at a genomic scale. Here, we use single-cell RNA-seq to investigate the molecular mechanisms governing heterogeneity and pathogenicity of Th17 cells isolated from the central nervous system (CNS) and lymph nodes (LN) at the peak of autoimmune encephalomyelitis (EAE) or polarized in vitro under either pathogenic or non-pathogenic differentiation conditions. Computational analysis reveals a spectrum of cellular states in vivo, including a self-renewal state, Th1-like effector/memory states and a dysfunctional/senescent state. Relating these states to in vitro differentiated Th17 cells, unveils genes governing pathogenicity and disease susceptibility. Using knockout mice, we validate four novel genes: Gpr65, Plzp, Toso and Cd5l (in a companion paper). Cellular heterogeneity thus informs Th17 function in autoimmunity, and can identify targets for selective suppression of pathogenic Th17 cells while sparing non-pathogenic tissue-protective ones. Population transcriptional profiling of in vitro polarized Th17 cells, either sorted for IL17A/GFP+ or unsorted.

2015-11-20 | E-GEOD-75103 | biostudies-arrayexpress

Single-cell transcriptional profiling of Th17 cells, differentiated in vitro for 48h [IL1B_IL6_IL23-48h-IL-17A/GFP+]

2015-11-20 | E-GEOD-75109 | biostudies-arrayexpress

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