Transcriptional profile of thymic and splenic regulatory T cells, sufficient and deficient in miR-181a
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PROVIDER: PRJNA474813 | ENA |
REPOSITORIES: ENA
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Project description:MicroRNAs (miRNAs) are expressed from a class of small non-protein coding RNA molecules. Growing evidence shows that miRNAs are potent mediators of post-transcriptional gene silencing and emerged to be critical in the regulation of innate and adaptive immune responses (Ansel KM, Immunol Rev 2013, p5; Baumjohann D, Nature Rev Immunol 2013, p666). MicroRNA-181a (miR-181a) constitutes the most prominently expressed miRNA species in DP thymocytes (Neilson JR, Genes Dev 2007, p578; Kirigin FF, JI 2012, p3257) and has been associated with modulating TCR signal strength via targeting serine/threonine as well as tyrosine phosphatases (Li Q-J, Cell 2007, p147). Consequently, elevated expression of miR-181a results in reduced phosphatase activity and increased TCR signal strength. The effect of aberrant expression of miR-181a on TCR signaling has been already analyzed employing short-term assays and in vitro organ cultures. Our group started to investigate the consequences of miR-181a/b-1 deletion on T cell development in vivo in the steady state. To this end, we developed a new mouse model - miR-181a/b-1 knockout mice (Zietara N et al, PNAS 2013b). During investigations of the immune system of miR-181a/b-1 deficient mice we discovered that these miRNAs are critical for the development of invariant natural killer (NK) T cells. Such cells are known to be selected by a high affinity agonist ligands, thus they are particularly sensitive to the modulation of TCR signaling thresholds, which is achieved by miR-181a/b-1 (Zietara N et al, PNAS 2013b). Furthermore we hypothesized that similar regulation might apply for the other T cell populations selected under high TCR signal strength, like Treg cells. Thus our current research focuses on the role of miR-181a/b-1 during Treg cell development in the thymus as well as on their function in the periphery.
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Human lymphoblastoid cells: HLA-DR immunopeptidome identified from different cell dilutions.
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Project description:The interdependence of selective cues during development of regulatory T (Treg) cells in the thymus and their suppressive function remains incompletely understood. Here we analyzed this interdependence by taking advantage of highly dynamic changes of miR-181a/b-1 during late T-cell development with very high levels of expression during thymocyte selection followed by massive downregulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus, but simultaneiously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1-deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of CTLA-4 protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.
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Project description:We have identified a single miRNA, miR-181a, that can modulate TGF-β signaling to induce and maintain EMT, and effect further downstream events of tumour cell survival, altered response to chemotherapy, migration, invasion and dissemination in vivo. Our present study provides an understanding of how enhanced expression of miR-181a can confer malignant and invasive traits through the modulation of a canonical signaling pathway and a consequent maintenance of a mesenchymal state. Furthermore, inhibition of miR-181a led to a reversion of EMT and subsequent events through decreased TGF-β signaling. Our data confirmed Smad7 as a functional target through which TGF-β-mediated EMT occurs; re-expression of Smad7 lacking its 3'UTR was able to rescue miR-181a-mediated phenotypes, deeming Smad7 as a critical mediator of miR-181a-induced EMT. Other recent studies support the crucial role(s) that miRNAs play in mediating EMT and consequent aggressive disease traits. For example, the miR-106b-25 cluster has also been shown to target Smad7 and mediate TGF-β-induced EMT downstream to Six1 in breast cancer34. miR-9 directly targets E-cadherin and inhibition of miR-9 had led to an inhibition of metastasis35. Conversely, the miR-200 and -205 family was shown to target transcriptional repressors of E-cadherin, ZEB1 and SIP1, and re-expression of these miRNAs led to a mesenchymal-to-epithelial transition and prevented TGF-β -induced EMT36. A2780 ovarian cancer cell lines stably expressing either pBABE (control vector), p181a#1( clone 1 expressing miR-181a) or p181a#2( clone 2 expressing miR-181a)
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Project description:This series consists of samples taken from two groups of K562 cells(miR-181a transfected group and control group ) and harvested 48 hours later. We used Agilent human 1A oligo microarray identified the changes in gene expression profile of K562 cells after miR-181a transfection experiment. Further studies aimed to find target mRNA of miR-181a in mammalian cells and its biological function. Keywords = miR-181a Keywords = microarray Keywords = K562 Keywords: microRNA transfection analysis
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Project description:We have identified a single miRNA, miR-181a, that can modulate TGF-β signaling to induce and maintain EMT, and effect further downstream events of tumour cell survival, altered response to chemotherapy, migration, invasion and dissemination in vivo. Our present study provides an understanding of how enhanced expression of miR-181a can confer malignant and invasive traits through the modulation of a canonical signaling pathway and a consequent maintenance of a mesenchymal state. Furthermore, inhibition of miR-181a led to a reversion of EMT and subsequent events through decreased TGF-β signaling. Our data confirmed Smad7 as a functional target through which TGF-β-mediated EMT occurs; re-expression of Smad7 lacking its 3'UTR was able to rescue miR-181a-mediated phenotypes, deeming Smad7 as a critical mediator of miR-181a-induced EMT. Other recent studies support the crucial role(s) that miRNAs play in mediating EMT and consequent aggressive disease traits. For example, the miR-106b-25 cluster has also been shown to target Smad7 and mediate TGF-β-induced EMT downstream to Six1 in breast cancer34. miR-9 directly targets E-cadherin and inhibition of miR-9 had led to an inhibition of metastasis35. Conversely, the miR-200 and -205 family was shown to target transcriptional repressors of E-cadherin, ZEB1 and SIP1, and re-expression of these miRNAs led to a mesenchymal-to-epithelial transition and prevented TGF-β -induced EMT36.
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