MiR-148a-3p and DDX6 functional link promotes survival of myeloid leukemia cells
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ABSTRACT:
PROVIDER: PRJNA833443 | ENA |
REPOSITORIES: ENA
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Project description:Post-transcriptional regulation of genes is heavily dependent on the action of miRNAs. miRNAs take part in various cellular processes and have been shown to be crucial in oncogenesis. Identification of miRNA targets is crucial for understanding its functions in different cellular contexts. miR-148a-3p is highly expressed in HCT116 cells and several other cell lines. However, the studies about mRNA targetting activitiy of this miRNA was limited. In this study, we aimed at identifying target repotoire of miR-148a-3p by using HCT116 DROSHA-KO model. We found several genes that are under miR-148a-3p regulation, including several reported targets. We next found the negative association between miR-148a-3p and DDX6, one of the identified gene, in leukemia. We examined DDX6 functions in this cancer and showed that the depletion of DDX6 helps impair leukemia cell growth, promote apoptosis and increase survival rate of transplanted mice. We then identified that DDX6 functions to suppress TXNIP, a well known tumor suppressor in leukemia and various types of cancer. Our findings uncovered the regulation axis between miR-148a-3p/DDX6/TXNIP in leukemia which provides molecular mechanism basis for therapeutic treatment directions.
2022-06-07 | GSE201905 | GEO
Project description:Purpose: To investigate the regulatory role of microRNA (miR)-148a-3p in mouse corpus cavernous pericyte (MCPs)-derived extracellular vesicles (EVs) in the treatment of diabetes-induced erectile dysfunction (ED). Materials and Methods: Mouse corpus cavernous tissue was used for MCPs primary culture and EVs isolation. Small RNA sequencing analysis was performed to assess the type and content of miRs in MCPs-EVs. Four groups of mice were used: control nondiabetic mice and streptozotocin-induced diabetic mice receiving two intracavernous injections (days -3 and 0) of phosphate buffered saline, MCPs-EVs transfected with regent control, or MCPs-EVs transfected with miR-148a-3p inhibitor. The function of miR-148a-3p in MCPs-EVs was evaluated by tube formation assay, migration assay, TUNEL assay, intracavernous pressure, immunofluorescence staining, and western blot experiments. Results: We extracted EVs from MCPs and by small RNA sequencing analysis we found that miR-148a-3p is enriched in MCPs-EVs. Exogenous administration of MCPs-EVs can effectively promote mouse cavernous endothelial cell (MCECs) tube formation, migration, proliferation, and reduce MCECs apoptosis under high-glucose conditions. However, these effects are significantly attenuated in miR-148a-3p-depleted MCPs-EVs, which is extracted after inhibiting miR-148a-3p expression in MCPs. Repeated intracavernous injections of MCPs-EVs improves erectile function by inducing cavernous neurovascular regeneration in diabetic mice. Through online bioinformatics databases and luciferase report assays, we predict Pyruvate dehydrogenase kinase-4 (PDK4) is a potential target gene of miR-148a-3p. Conclusions: Our findings provide new and reliable evidence that miR-148a-3p in MCPs-EVs significantly enhances cavernous neurovascular regeneration by inhibiting PDK4 in diabetic mice.
2023-12-19 | GSE195533 | GEO
Project description:We performed a genome-scale screen for suppressors of interferon stimulated gene (ISG) expression in human haploid cells (HAP1). DEAD-box helicase 6 (DDX6) was a significant hit. In order to validate DDX6 as a regulator of ISG expression, we created knockouts of DDX6 in HAP1 cells using CRISPR-Cas9 and performed RNA-seq on coding RNA from DDX6 KO and WT cells. This data was used to determine if ISGs were upregulated in DDX6 KO HAP1 cells.
2017-07-25 | E-MTAB-5867 | biostudies-arrayexpress
Project description:Long-lived antibody-secreting plasma cells are essential to establish humoral memory against pathogens. While a plasma cell gene signature has been established, elaborate key regulators remain enigmatic.The plasma cell signature microRNA miR-148a favors in vitro differentiation of plasmablasts by repressing the germinal center transcription factor Bach2 and pro-apoptotic BIM and PTEN. To determine whether miR-148a fine-tunescontrols the in vivo development of B cells into long-lived plasma cells, we established mice with a genomic, conditional and inducible deletion of miR-148a. The analysis of miR-148a-deficient mice revealed reduced serum Ig, decreased numbers of newly formed plasmablasts and a reduced CD19-negative, CD93-positive long-lived plasma cells compartment. RNASeq and metabolic analysis showed an impaired glucose uptake and oxidative phosphorylation-based energy metabolism, altered abundance of homing receptors CXCR3 (increase) and CXCR4 (reduction) in miR-148a-deficient plasma cells. These findings establish the importance of miR-148a as a regulator of the differentiation and maintenance of late CD19-negative mature plasma cells by controlling their metabolism and retention in the bone marrow niche. clearly undermine our model of miR-148a as a regulator of the maintenance of long-lived plasma cells.
2021-05-21 | GSE156002 | GEO
Project description:A quantitative proteomics combined with stable isotope labeling was applied to identify the global profile of miR-148a-regulated downstream proteins in AGS cancer cells. For proteomic analysis, cells were treated with miR-148a mimic (Pre-miR-148a) or miR-148a negative control (miR-CTL) and the downstream protein expression level (Pre-miR-148a/miR-CTL) were quantified using iTRAQ approach. Bioinformatics pipeline: The peak list in the resultant MS/MS spectra were generated by Mascot Distiller v2.1.1.0 and searched using Mascot v2.2 against the International Protein Index (IPI) human database (v. 3.64, 84032 sequences). The Mascot search parameters were +-0.1 Da for MS tolerance, +-0.1 Da for MS/MS mass tolerance, allowances for two missed cleavages, and variable modifications of deamidation (NQ), oxidation (M), iTRAQ (N terminal), iTRAQ (K), and MMTS (C). Protein quantitation were calculated using the Multi-Q software v1.6.5.4 with a dynamic range filter of ion count > 30.
2013-07-24 | PXD000190 | Pride
Project description:Recent findings indicate that the translation elongation rate influences mRNA stability. One of the factors that has been implicated in this link between mRNA decay and translation speed is the yeast DEAD-box helicase Dhh1p. Here, we demonstrate that the human ortholog of Dhh1p, DDX6, triggers deadenylation-dependent decay of inefficiently translated mRNAs in human cells. DDX6 interacts with the ribosome through the Phe-Asp-Phe (FDF) motif in its RecA2 domain. Furthermore, RecA2-mediated interactions and ATPase activity are both required for DDX6 to destabilize inefficiently translated mRNAs. Using ribosome profiling and RNA sequencing, we identified two classes of endogenous mRNAs that are regulated in a DDX6-dependent manner. The identified targets are either translationally regulated or regulated at the steady-state-level and either exhibit signatures of poor overall translation or of locally reduced ribosome translocation rates. Transferring the identified sequence stretches into a reporter mRNA caused translation- and DDX6-dependent degradation of the reporter mRNA. In summary, these results identify DDX6 as a crucial regulator of mRNA translation and decay triggered by slow ribosome movement and provide insights into the mechanism by which DDX6 destabilizes inefficiently translated mRNAs.
2024-01-23 | GSE231964 | GEO
Project description:DDX6 is an abundant cytoplasmic DEAD-box RNA helicase which is involved in disparate aspects of mRNA stability and translation, leading to a confused understanding of its global function. We carried out a large-scale study of total and polysomial mRNA after DDX6 depletion to get an accurate picture of its roles in human cells.
2017-09-28 | E-MTAB-4091 | biostudies-arrayexpress
Project description:miR-148a controls metabolic programming and survival of mature CD19-negative plasma cells
| PRJNA656296 | ENA
Project description:DDX6 is an RNA helicase and involved in various post-transcriptional regulatory processes. Although DDX6 is an evolutionarily well conserved central player in post-transcriptional gene regulation, its function in embryonic development remains obscure. To study this, we examined Ddx6 knockout mouse embryos and pluripotent cell lines. E8.5 Ddx6 mutants exhibited gastrulation defects. To transcriptomically identify the existing cell population in E8.5 mutant embryos and further find the possible causes of this defect, we performed RNA-seq analysis with E8.5 embryo cDNA libraries.
2022-08-22 | GSE171156 | GEO
Project description:A microRNA signature for early detection and RNA therapy in Alzheimer´s disease (miR-148a-3p)
| PRJNA641433 | ENA