DDX5 RNA interactome in cultured T cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE157259 | GEO | 2022/12/21
REPOSITORIES: GEO
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Project description:The high rates of mortality associated with epithelial ovarian cancer (EOC) are a direct consequence of its metastatic nature. Metastasis is dependent on many factors, among which activation of angiogenesis is most significant. Angiogenesis is, in turn, contingent upon the cellular response to hypoxia within the tumor microenvironment. Hypoxia-inducible factor 1 (HIF1) is a transcription factor composed of HIF1alpha and HIF1beta subunits and is the master regulator of the hypoxic response. It is therefore a critical mediator of tumor angiogenesis and metastasis. Regulation of HIF1 is primarily at the level of protein. In normoxia, the HIF1alpha subunit is hydroxylated via an oxygen- and iron-dependent mechanism and targeted for destruction. In hypoxia, low oxygen levels preclude hydroxylation and HIF1alpha is stabilized, allowing for its association with constitutively expressed HIF1beta to form bioactive HIF1. We have identified a novel mechanism of HIF1alpha regulation in EOC cells that involves microRNAs (miRs), ~22 nucleotide, non-coding RNA molecules that repress translation of target mRNAs by binding their 3’ untranslated regions (UTRs). Using microarray and qPCR analysis, we found that levels of miR-199a-1, a miR that is predicted in silico to target the HIF1alpha 3’ UTR, were reduced under hypoxia in EOC cells. We further demonstrated that miR-199a-1 directly targets the HIF1alpha 3’ UTR and overexpression of miR-199a-1 suppresses HIF1alpha protein levels and HIF1-driven gene expression. Moreover, cells stably overexpressing miR-199a-1 exhibit marked defects in migratory ability. These data were corroborated by our in vivo findings, which demonstrated that overexpression of miR-199a-1 causes significant reductions in tumor vessel density and tumor burden in nude mice. These findings provide insight into non-canonical, miR- and iron-based mechanisms of HIF1 regulation that may have important implications in the progression of EOC. miRNA expression analysis of A2780 epithelial ovarian cancer cells by microarrays
2011-09-23 | E-GEOD-32313 | biostudies-arrayexpress
Project description:The high rates of mortality associated with epithelial ovarian cancer (EOC) are a direct consequence of its metastatic nature. Metastasis is dependent on many factors, among which activation of angiogenesis is most significant. Angiogenesis is, in turn, contingent upon the cellular response to hypoxia within the tumor microenvironment. Hypoxia-inducible factor 1 (HIF1) is a transcription factor composed of HIF1alpha and HIF1beta subunits and is the master regulator of the hypoxic response. It is therefore a critical mediator of tumor angiogenesis and metastasis. Regulation of HIF1 is primarily at the level of protein. In normoxia, the HIF1alpha subunit is hydroxylated via an oxygen- and iron-dependent mechanism and targeted for destruction. In hypoxia, low oxygen levels preclude hydroxylation and HIF1alpha is stabilized, allowing for its association with constitutively expressed HIF1beta to form bioactive HIF1. We have identified a novel mechanism of HIF1alpha regulation in EOC cells that involves microRNAs (miRs), ~22 nucleotide, non-coding RNA molecules that repress translation of target mRNAs by binding their 3’ untranslated regions (UTRs). Using microarray and qPCR analysis, we found that levels of miR-199a-1, a miR that is predicted in silico to target the HIF1alpha 3’ UTR, were reduced under hypoxia in EOC cells. We further demonstrated that miR-199a-1 directly targets the HIF1alpha 3’ UTR and overexpression of miR-199a-1 suppresses HIF1alpha protein levels and HIF1-driven gene expression. Moreover, cells stably overexpressing miR-199a-1 exhibit marked defects in migratory ability. These data were corroborated by our in vivo findings, which demonstrated that overexpression of miR-199a-1 causes significant reductions in tumor vessel density and tumor burden in nude mice. These findings provide insight into non-canonical, miR- and iron-based mechanisms of HIF1 regulation that may have important implications in the progression of EOC.
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Project description:Abstract: Regulatory T cells (Tregs) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Tregs subvert beneficial anti-tumor immunity by modulating inhibitory receptor (IR) expression on tumor infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms remain elusive. Here we show that interleukin-10 (IL10) and interleukin-35 (IL35; a heterodimer of Ebi3 and IL12) are reciprocally expressed by Treg-subpopulations in the tumor microenvironment (TME) and cooperatively promote intratumoral T cell exhaustion. Treg-restricted deletion of either Il10/Ebi3 or dual deletion resulted in delayed tumor growth and significant reduction of transcriptomic exhaustion signature associated with reduced expression of B lymphocyte-induced maturation protein-1 (BLIMP1; Prdm1). While the two cytokines share the BLIMP1 axis to drive multi-IR expression; they differentially impact effector vs. memory fate, highlighting their overlapping and non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated adaptive plasticity in inhibitory cytokine expression pattern by Tregs in TME for maximal immunosuppression. Data purpose: to understand the segregated cytokine expression pattern and the preferential generation of single cytokine positive Treg subpopulations, we performed single cell RNASeq (scRNAseq) contrasting Tregs isolated from naïve, unchallenged LNs or day 14 B16 tumor from Foxp3Cre-YFP WT mice
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Project description:Foxp3+ regulatory T (Treg) cells are essential for immunological tolerance and homeostasis. In peripheral tissues, Treg cells acquire enhanced suppressive functions and co-opt distinct transcriptional modules, allowing context and tissue-dependent immune regulation. Here we show that the transcription factor c-Maf was highly expressed by effector Treg cells and controlled their IL-10 production. In the intestine, c-Maf was required for the differentiation of RORgt+ microbiota-dependent Treg cells, and restricted their production of inflammatory cytokines. Consequently, Treg cell-specific loss of c-Maf resulted in perturbed intestinal homeostasis, microbial dysbiosis and a selective failure to control Th17 responses during homeostasis and upon chemically induced epithelial damage. Molecular profiling revealed that c-Maf regulated expression of key genes of the transcriptional signature of intestinal Treg cells, including Rorc and Il10. Thus, our study identifies a key role of c-Maf in preserving the identity and function of intestinal Treg cells, essential for the control of intestinal immune homeostasis.
2018-12-18 | GSE106396 | GEO
Project description:RNA-Seq analysis of Treg cell subsets isolated from lungs of Il10GFPFoxp3Thy1.1 mice. Thy1.1+ Treg cells were FACS-sorted into IL-10–IL-18R–, IL-10+IL-18R– and IL10–IL-18R+ populations on day 5 following intranasal infection with 0.5 LD50 PR8-OTI influenza virus. mRNA profiles of each Thy1.1+ Treg cell population (IL-10–IL-18R–, IL-10+IL-18R– and IL10–IL-18R+) from lungs on day 5 following influenza infection from 5 infected mice, sorted into TRIzol LS reagent.
2015-08-27 | E-GEOD-71588 | biostudies-arrayexpress
Project description:Regulatory T cells (Tregs) play a critical role in the maintenance of immunological self-tolerance. Naïve human or murine T cell treatment with the inhibitory cytokine IL35 induces a regulatory population, termed iTR35, that mediates suppression via IL35, but not IL10 or TGFβ, neither express nor require Foxp3, are strongly suppressive in five in vivo models, and exhibit in vivo stability. Treg-mediated suppression induces iTR35 generation in an IL35- and IL10-dependent manner in vitro, and in inflammatory conditions in vivo in Trichuris-infected intestines and within the tumor microenvironment, where they appear to contribute to the regulatory milieu. iTR35 may constitute a key mediator of infectious tolerance and may contribute to Treg-mediated tumor progression, and ex vivo-generated iTR35 may possess therapeutic utility. Five IL35-treated samples, in parallel with 5 control-treated samples, were compared to 3 Treg and 3 Tconv cell samples.
2010-09-18 | E-GEOD-24210 | biostudies-arrayexpress
Project description:The tumor microenvironment contains high frequencies of inflammatory regulatory T (Treg) cells. These Treg exhibit superior regulatory function compared with those from other environments such as the spleen, partially due to expression of anti-inflammatory interleukin-10. In order to gain insight into the origins and functional roles of different Treg subsets, we used whole genome microarray analysis to characterize tumor IL-10+ and tumor IL-10- Treg subsets obtained from VERT-X reporter mice bearing transplantable tumors, along with total tumor Treg and spleen Treg from FoxP3-EGFP reporter mice. Few genes were found to differ between IL-10+ and IL-10- tumor Treg subsets (29 upregulated, 88 downregulated), suggesting a common origin of each Treg subset. The specific gene expression profile of IL-10+ tumor Treg was associated with the tumor microenvironment and absent from spleen Treg, suggesting it to be driven by components of the inflammatory tumor microenvironment. The IL-10+ tumor Treg gene expression profile displayed upregulation of genes associated with a higher activation state and greater effector function. Pooled MC38 tumor tissue from VERT-X or FoxP3-EGFP reporter mice were used to obtain IL10+ tumor Treg (VERT-X), IL10- tumor Treg (VERT-X) and total tumor Treg (FoxP3-EGFP). Spleens from tumor-free FoxP3-EGFP mice were used for spleen Treg. Three experiments for each population gave a total 12 RNA samples.
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Project description:Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX to those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multi-omic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs lost their phenotypic and functional markers including CD25 and often also FOXP3. Functional experiments with CRISPR/Cas9-mediated FOXP3 knock-out Treg and Tregs from patients with IPEX indicated that the patients’ Tregs gain a Th2 skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation, indicated that Tregs expressing non-mutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. Collectively, we describe Treg instability and Teff autoreactivity in patients with IPEX. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.
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