Analysis of miRNA expression patterns in tetracycline (Tet) inducible Scl/tTA-BCR/ABL (Scl-BA) transgenic mouse hematopoietic stem-progenitor cells.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE122432 | GEO | 2021/06/30
REPOSITORIES: GEO
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Project description:MiR-142 is dynamically expressed and plays a regulatory role in hematopoiesis. Based on the simple observation that miR-142 levels are significantly lower in CD34+CD38- cells from blast crisis (BC) chronic myeloid leukemia (CML). CML patients compared with chronic phase (CP) CML patients (p=0.002), we hypothesized that miR-142 deficit plays a role in BC transformation. To test this hypothesis, we generated a miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mouse by crossing a miR-142−/− mouse with a miR-142+/+BCR-ABL mouse. While the miR-142+/+BCR-ABL mice developed and died of CP CML, the miR-142−/−BCR-ABL mice developed a BC-like phenotype in the absence of any other acquired gene mutations and died significantly sooner than miR-142+/+BCR-ABL CP controls (p=0.001). Leukemic stem cell (LSC)-enriched Lineage-Sca-1+c-Kit+ cells (LSKs) from diseased miR-142−/−BCR-ABL mice transplanted into congenic recipients, recapitulated the BC features thereby suggesting stable transformation of CP-LSCs into BC-LSCs in the miR-142 KO CML mouse. Single cell (sc) RNA-seq profiling showed that miR-142 deficit changed the cellular landscape of the miR-142−/−BCR-ABL LSKs compared with miR-142+/+BCR-ABL LSKs with expansion of myeloid-primed and loss of lymphoid-primed factions. Bulk RNA-seq analyses along with unbiased metabolomic profiling and functional metabolic assays demonstrated enhanced fatty acid β-oxidation (FAO) and oxidative phosphorylation (OxPhos) in miR-142−/−BCR-ABL LSKs vs miR-142+/+BCR-ABL LSKs. MiR-142 deficit enhanced FAO in miR-142−/−BCR-ABL LSKs by increasing the expression of CPT1A and CPT1B, that controls the cytosol-to-mitochondrial acyl-carnitine transport, a critical step in FAO. MiR-142 deficit also enhanced OxPhos in miR-142−/−BCR-ABL LSKs by increasing mitochondrial fusion and activity. As the homeostasis and activity of LSCs depend on higher levels of these oxidative metabolism processes, we then postulate that miR-142 deficit is a potentially druggable target for BC-LSCs. To this end, we developed a novel CpG-miR-142 mimic oligonucleotide (ODN; i.e., CpG-M-miR-142) that corrected the miR-142 deficit and alone or in combination with a tyrosine kinase inhibitor (TKI) significantly reduced LSC burden and prolonged survival of miR-142−/−BCR-ABL mice. The results from murine models were validated in BC CD34+CD38- primary blasts and patient-derived xenografts (PDXs). In conclusion, an acquired miR-142 deficit sufficed in transforming CP-LSCs into BC-LSCs, via enhancement of bioenergetic oxidative metabolism in absence of any additional gene mutations, and likely represent a novel therapeutic target in BC CML.
2023-01-13 | ST002446 | MetabolomicsWorkbench
Project description:iPSC-derived neurons were treated with mimics and inhibitors of the miRNAs miR-150-5p, hsa-mir-193a-3p and hsa-miR-19b-3p.
RNA-sequencing was then performed to examine the effects of miRNA up-regulation and inhibition.
| EGAD00001006844 | EGA
Project description:Purpose: We report the application of NGS for the impacts of BDE47 exposure on the miRNA expression profiling of zebrafish larvae. Methods: miRNA profiles of 6-day-old BDE47-treated and control zebrafish larvae were generated by deep sequencing using Illumina Hisq 2000 platform. The sequence reads that passed quality filters were analyzed at the transcript isoform level with TopHat followed by Cufflinks. Results: Compared BDE47 treatments with solvent control, a dozen of validated zebrafish miRNAs, including dre-miR-142a-3p, dre-miR-142b-5p, dre-miR-144-3p, dre-miR-146a, dre-miR-190a, dre-miR-219-5p, dre-miR-301b-3p, dre-miR-459-5p, rno-miR-33-5p, dre-miR-735-3p, and dre-miR-735-5p, significantly changed their expressions. Conclusions: This study provides a framework for the application of high-throughput sequencing towards characterization of the impacts of BDE47 on whole zebrafish larval miRNA expression profiling.
2017-01-12 | GSE84845 | GEO
Project description:Our objective is to decipher a miRNA expression signature associated with Chronic myeloid leukemia (CML), with or without Imatinib or Dasatinib and compared to normal blood leukocytes, and to determine potential target genes and signaling pathways affected by these signature miRNAs. Background/Aims: MicroRNAs (miRNAs) are short non-coding regulatory RNAs that control gene expression and play an important role in cancer development and progression. However, little is known about the role of miRNAs in chronic myeloid leukemia (CML). Our objective is to decipher a miRNA expression signature associated with CML and to determine potential target genes and signaling pathways affected by these signature miRNAs. Results: Using miRNA microarrays we characterized the miRNAs expression profile of K562 cells in reference to healthy blood. We also looked into the expression profile of K562 cells treated with imatinib or dasatinib. We identified a miRNA signature that distinguishes K562 cells from healthy blood that included downregulation of miRNAs such as miR-31, miR-34a, miR-143, miR-145, miR-155, miR-196b and miR-564 and upregulation of miR-128. We also identified a miRNA signature that distinguishes untreated K562 cells from the treated ones that included downregulation of miRNAs such as miR-128 and upregulation of miR-564. Results: Using miRNA microarrays we characterized the miRNAs expression profile of K562 cells in reference to healthy blood. We also looked into the expression profile of K562 cells treated with imatinib or dasatinib. We identified a miRNA signature that distinguishes K562 cells from healthy blood that included downregulation of miRNAs such as miR-31, miR-34a, miR-143, miR-145, miR-155, miR-196b and miR-564 and upregulation of miR-128. We also identified a miRNA signature that distinguishes untreated K562 cells from the treated ones that included downregulation of miRNAs such as miR-128 and upregulation of miR-564. We next analyzed predicted targets and affected pathways of the deregulated miRNAs. Reassuringly, the analysis identified CML as the main disease associated with these miRNAs. MAPK, TGF-beta and Wnt were the main molecular pathways related with these expression patterns. Utilizing Venn diagrams we found appreciable overlap between the CML-related miRNAs and the MAPK and TGF-beta signaling pathways and focal adhesion-related miRNAs. Conclusions: The miRNAs identified in this study might offer a pivotal role in CML. Nevertheless, while these data point to a central disease, the precise molecular pathway/s targeted by these miRNAs is variable implying a high level of complexity of miRNA target selection and regulation. These deregulated miRNAs highlight new candidate gene targets allowing for a better understanding of the molecular mechanism underlying the development of CML, and propose possible new avenues for therapeutic treatment. MiRNA profiling of CML: With the objective of deciphering a potential miRNA expression signature associated with CML, we analyzed the miRNAs expression profile of K562 in reference to a pool of 3 healthy blood samples using an miRNA-based microarray chip assay. In addition, to search for Bcr-Abl-dependent or Src-dependant miRNA expression patterns, K562 cells were treated or not with imatinib or with dasatinib to inhibit Bcr-Abl tyrosine kinase activity or Bcr-Abl and Src tyrosine kinase activity, respectively. In order to validate the microarray data and to ensure that the variability observed among samples was not technical, we carried out Taqman miRNA quantitative real-time PCR analysis (Applied Biosystems, USA) on miRNAs that we find to be most relevant, according to bioinformatics analysis (see below) and published data.
2011-10-20 | E-GEOD-28825 | biostudies-arrayexpress
Project description:To assess how the miR-142 deficit affected the BM LSC-enriched LSK landscape, we conducted a single cell RNA-seq analysis of BM miR-142+/+ BCR-ABL (CP CML) and miR-142−/− BCR-ABL (BC CML) LSKs which were harvested from the respective mice, 2 weeks after BCR-ABL induction.
2022-11-02 | GSE217076 | GEO
Project description:To gain insight into how miR-142 deficit drives a BC-like transformation, we performed RNA-seq on bone marrow (BM) Lin-Sca-1+c-Kit+ cells (LSKs) harvested from normal miR-142+/+ (wt) and miR-142−/− (miR-142 KO) mice, as well as from leukemic miR-142+/+ BCR-ABL (CP CML) and miR-142−/− BCR-ABL (BC CML) mice, two weeks after BCR-ABL induction. We then performed gene expression profiling analysis using data obtained from RNA-seq of 24 samples of LSK cells from 4 mouse strains (KO vs WT, KO CML vs CML).
2022-11-01 | GSE216794 | GEO
Project description:Background: Newer 3D culturing approaches are a promising way to better mimic the in vivo tumor microenvironment and to study the interactions between the heterogeneous cell populations of glioblastoma multiforme. Like many other tumors, glioblastoma uses extracellular vesicles as an intercellular communication system to prepare surrounding tissue for invasive tumor growth. However, little is known about the effects of 3D culture on extracellular vesicles. The aim of this study was to comprehensively characterise extracellular vesicles in 3D organoid models and compare them to conventional 2D cell culture systems.Methods: Primary glioblastoma cells were cultured as 2D and 3D organoid models. Extracellular vesicles were obtained by precipitation and immunoaffinity, with the latter allowing targeted isolation of the CD9/CD63/CD81 vesicle subpopulation. Comprehensive vesicle characterisation was performed and miRNA expression profiles were generated by smallRNA-sequencing. In silico analysis of differentially regulated miRNAs was performed to identify mRNA targets and corresponding signaling pathways. The tumor cell media and extracellular vesicle proteome were analysed by high-resolution mass spectrometry.Results: We observed an increased concentration of extracellular vesicles in 3D organoid cultures. Differential gene expression analysis further revealed the regulation of twelve miRNAs in 3D tumor organoid cultures (with nine miRNAs down and three miRNAs upregulated). MiR-23a-3p, known to be involved in glioblastoma invasion, was significantly increased in 3D. MiR-7-5p, which counteracts glioblastoma malignancy, was significantly decreased. Moreover, we identified four miRNAs (miR- 323a-3p, miR-382-5p, miR-370-3p, miR-134-5p) located within the DLK1-DIO3 domain, a cancer associated genomic region, suggesting a possible importance of this region in glioblastoma progression. Overrepresentation analysis identified alterations of extracellular vesicle cargo in 3D organoids, including representation of several miRNA targets and proteins primarily implicated in the immune response.Conclusion: Our results show that 3D glioblastoma organoid models secrete extracellular vesicles with an altered cargo compared to corresponding conventional 2D cultures. Extracellular vesicles from 3D cultures were found to contain signaling molecules associated with the immune regulatory signaling pathways and as such could potentially change the surrounding microenvironment towards tumor progression and immunosuppressive conditions. These findings suggest the use of 3D glioblastoma models for further clinical biomarker studies as well as investigation of new therapeutic options.
2024-04-09 | PXD047328 | Pride
Project description:Microglia were derived from iPSCs and treated with mimics and inhibitors of the miRNAs hsa-miR-150-5p, hsa-miR-193a-3p and hsa-miR-19b-3p. RNA-sequencing was then performed to examine the effects of up- and down-regulation of the respective miRNAs.
| EGAD00001006842 | EGA
Project description:Non-thermal plasma, a partially ionized gas, holds significant potential for clinical applications, including wound healing support, oral therapies, and anti-tumour treatments. While its applications shown promising outcomes, the underlying molecular mechanisms remain incompletely understood. We thus applied non-thermal plasma to mouse auricular skin and conducted non-coding RNA sequencing, as well as single-cell blood sequencing. In a time-series analysis (5 time points spanning 2 hours), we compared the expression of microRNAs in the plasma-treated left ears to the unexposed right ears of the same mice as well as to the ears of unexposed control mice. Our findings indicate specific effects in the treated ears for a set of five miRNAs: mmu-miR-144-5p, mmu-miR-144-3p, mmu-miR-142a-5p, mmu-miR-223-3p, and mmu-miR-451a. Interestingly, miR-223-3p also exhibited an increase over time in the right non-treated ear of the exposed mice, suggesting systemic effects. Notably, this miRNA, along with mmu-miR-142a-5p and mmu-miR-144-3p, regulates genes and pathways associated with wound healing and tissue regeneration (namely ErbB, FoxO, Hippo, and PI3K-Akt signalling). This co-regulation is particularly remarkable considering the significant seed dissimilarities among the miRNAs. Finally, single blood cell sequencing revealed the downregulation of 12 from 15 target genes in B-cells, Cd4+ and Cd8+ T-cells. Collectively, our data provide evidence for a systemic effect of non-thermal plasma.
2023-07-12 | GSE236788 | GEO
Project description:Non-thermal plasma, a partially ionized gas, holds significant potential for clinical applications, including wound healing support, oral therapies, and anti-tumour treatments. While its applications shown promising outcomes, the underlying molecular mechanisms remain incompletely understood. We thus applied non-thermal plasma to mouse auricular skin and conducted non-coding RNA sequencing, as well as single-cell blood sequencing. In a time-series analysis (5 time points spanning 2 hours), we compared the expression of microRNAs in the plasma-treated left ears to the unexposed right ears of the same mice as well as to the ears of unexposed control mice. Our findings indicate specific effects in the treated ears for a set of five miRNAs: mmu-miR-144-5p, mmu-miR-144-3p, mmu-miR-142a-5p, mmu-miR-223-3p, and mmu-miR-451a. Interestingly, miR-223-3p also exhibited an increase over time in the right non-treated ear of the exposed mice, suggesting systemic effects. Notably, this miRNA, along with mmu-miR-142a-5p and mmu-miR-144-3p, regulates genes and pathways associated with wound healing and tissue regeneration (namely ErbB, FoxO, Hippo, and PI3K-Akt signalling). This co-regulation is particularly remarkable considering the significant seed dissimilarities among the miRNAs. Finally, single blood cell sequencing revealed the downregulation of 12 from 15 target genes in B-cells, Cd4+ and Cd8+ T-cells. Collectively, our data provide evidence for a systemic effect of non-thermal plasma.
2023-07-12 | GSE236801 | GEO