Similar Datasets
Project description:MicroRNAs (miRNAs) are critical post-transcriptional regulators in many biological processes. They act by guiding RNA-induced silencing complexes to miRNA response elements (MREs) in target mRNA, resulting in translational inhibition and/or mRNA degradation. Efficient targeting depends on a combination of biochemically established targeting rules and contextual factors of a given miRNA and cell type. Here, we generated a high-resolution map of miR-181 MREs to define the targeting rules of miRNA miR-181a/b-1 in murine T-cell development. We uncovered a broad array of novel functional targets of miR-181 and demonstrated that miR-181 acts predominantly through RNA destabilization. High-resolution analysis validated the dominance of seed matches. Critically, we also discovered a unique alternative seed match for miR-181 and identified a distinct group of targets controlled by translational inhibition. In conclusion, deep profiling of miRNA MREs in primary cells is critical to expand physiologically relevant miRNA targetomes and helps to establish context-dependent miRNA targeting rules.
2023-09-06 | GSE242304 | GEO
Project description:Parkinson’s disease (PD) is caused by loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although PD pathogenesis is not fully understood, studies implicate perturbations in gene regulation, mitochondrial function, and neuronal activity. MicroRNAs (miRs) are small gene regulatory RNAs that inhibit diverse subsets of target mRNAs, and several studies have noted miR expression alterations in PD brains. For example, miR-181a is abundant in brain and is increased in PD patient brain samples; however, the disease relevance of this remains unclear. Herein, we show that miR-181 target mRNAs are broadly down-regulated in aging and PD brains. To address if the miR‑181 family plays a role in PD pathogenesis, we generated adeno-associated viruses (AAV) to overexpress and inhibit miR-181 isoforms. After co-injection with AAV overexpressing alpha-synuclein (aSyn) into mouse SN (PD model), we found that moderate miR-181a/b overexpression exacerbated aSyn-induced DA neuronal loss, whereas miR‑181 inhibition was neuroprotective, relative to controls (GFP-alone and/or scrambled RNA). Also, prolonged miR-181 overexpression in SN alone elicited measurable neurotoxicity coincident with an increased immune response. RNA-seq analyses revealed that miR-181a/b inhibits genes involved in synaptic transmission, neurite outgrowth, and mitochondrial respiration, along with several genes having known protective roles and genetic links in PD.
2022-03-23 | GSE196441 | GEO
Project description:miR-181a1/b1, miR-181a2/b2, and miR-181c/d belong to a highly conserved family of microRNA clusters, yet their role in vivo is poorly understood. Here we show that the miR-181a1/b1 cluster is absolutely essential for NKT development and is a critical determinant of thymocyte proliferation, survival and T-cell receptor α locus rearrangement. Furthermore, while individual ablation of miR-181a2/b2 and miR-181c/d revealed no overt phenotypes, compound mutant mice lacking both miR-181a1/b1 and miR-181a2/b2 display decreased survival, reduced body weight, and abnormal B cell development. Mechanistically, we reveal that miR-181 regulates PTEN, a key tumor suppressor whose abundance determines key metabolic adaptations required to meet the biosynthetic demands of highly proliferative tissues. These results provide important insights into the physiological function of this family of microRNAs in vivo; moreover, it places miR-181 as a central regulator of the PI3K signaling pathway and cellular metabolism. Three sorted populations of double positive (DP) thymocytes from each of two conditions (WT and miR181a1/b1 -/- mice)
2014-04-09 | E-GEOD-41090 | biostudies-arrayexpress
Project description:Background: Oral squamous cell carcinoma (OSCC) is a common malignant tumor associated with poor prognosis. MicroRNAs (miRNAs) play crucial regulatory roles in the cancer development. However, the role of miRNAs in OSCC development and progression is not well understood. Methods: We sought to establish a dynamic Chinese hamster OSCC animal model, construct miRNA differential expression profiles of its occurrence and development, predict its targets, and perform functional analysis and validation in vitro. Results: Using expression and functional analyses, the key candidate miRNA (miR-181a-5p) was selected for further functional research, and the expression of miR-181a-5p in OSCC tissues and cell lines was detected. Subsequently, transfection technology and a nude mouse tumorigenic model were used to explore potential molecular mechanisms. miR-181a-5p was significantly downregulated in human OSCC specimens and cell lines, and decreased miR-181a-5p expression was observed in multiple stages of the Chinese hamster OSCC animal model. Moreover, upregulated miR-181a-5p significantly inhibited OSCC cell proliferation, colony formation, invasion, and migration; blocked the cell cycle; and promoted apoptosis. BCL2 was identified as a target of miR-181a-5p. BCL2 may interact with apoptosis- (BAX), invasion- and migration- (TIMP1, MMP2, and MMP9), and cell cycle-related genes (KI67, E2F1, CYCLIND1, and CDK6) to further regulate biological behavior. Tumor xenograft analysis indicated that tumor growth was significantly inhibited in the high miR-181a-5p expression group. Conclusions: Our findings indicate that miR-181a-5p can be used as a potential biomarker and provide a novel animal model for mechanistic research on oral cancer.
2023-01-10 | GSE222429 | GEO
Project description:Themis1, a recently described T-lineage specific protein, is essential for thymic positive and negative selection. Although Themis1 has been clearly identified as a component of the T cell antigen receptor (TCR) signalosome, its precise role in TCR signaling remains unclear. Here, we used quantitative proteomic and TCR signaling reporter mice to gain insight into Themis1 signaling function. Mass spectrometry analysis of the Themis1 interactome identified Grb2, SHP1 and Vav1 as the principal interacting partners of Themis1 in thymocytes. The dataset contains mass spectrometry results from the analysis of 6 different kind of AP-MS purifications (based on immunoprecipitation using a Themis1 antibody) starting from the following samples: - thymocytes from WT mice, non stimulated (noted WT NS) - thymocytes from WT mice, stimulated with pervanadate (noted WT P) - thymocytes from GRB2 +/- mice (with decreased expression of GRB2), non stimulated (noted GRB2 NS) - thymocytes from GRB2 +/- mice (with decreased expression of GRB2), stimulated with pervanadate (noted GRB2 P) - thymocytes from Themis1 -/- mice (knock-out for Themis1), non stimulated (noted KO NS) - thymocytes from Themis1 -/- mice (knock-out for Themis1), stimulated with pervanadate (noted KO P) Three biological replicates were prepared for these 6 different conditions (noted, 1,2,3), yielding 18 analyzed samples. Three technical nanoLC-MS runs were acquired for each sample (noted R1, R2, R3), leading to the 54 nanoLC-MS raw files contained in the dataset.
2017-02-06 | PXD004072 | Pride
Project description:miR-181a1/b1, miR-181a2/b2, and miR-181c/d belong to a highly conserved family of microRNA clusters, yet their role in vivo is poorly understood. Here we show that the miR-181a1/b1 cluster is absolutely essential for NKT development and is a critical determinant of thymocyte proliferation, survival and T-cell receptor α locus rearrangement. Furthermore, while individual ablation of miR-181a2/b2 and miR-181c/d revealed no overt phenotypes, compound mutant mice lacking both miR-181a1/b1 and miR-181a2/b2 display decreased survival, reduced body weight, and abnormal B cell development. Mechanistically, we reveal that miR-181 regulates PTEN, a key tumor suppressor whose abundance determines key metabolic adaptations required to meet the biosynthetic demands of highly proliferative tissues. These results provide important insights into the physiological function of this family of microRNAs in vivo; moreover, it places miR-181 as a central regulator of the PI3K signaling pathway and cellular metabolism.
2014-04-09 | GSE41090 | GEO
Project description:Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially. In addition, this data set has been used to identify a common prognostic gene signature (Li Z. et al. unpublished). 65 human AML samples bearing various cytogenetic and molecular abnormalities are used to identify miR-181 target genes and a common prognostic gene signature.
2012-04-03 | E-GEOD-30258 | biostudies-arrayexpress
Project description:Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially. In addition, this data set has also been used to identify a common prognostic gene signature in human AML (Li Z. et al., unpublished). 93 human AML samples bearing various cytogenetic and molecular abnormalities are used to identify miR-181 target genes and a common prognostic gene signature.
2012-04-03 | E-GEOD-30285 | biostudies-arrayexpress
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.
2019-02-08 | GSE115391 | GEO