Effects of miRNA-mediated TET2 in prostate cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE66038 | GEO | 2015/09/01
SECONDARY ACCESSION(S): PRJNA275742
REPOSITORIES: GEO
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Project description:Prostate cancer is the most common cancer in men. We identified that miR-29 family is the most androgen-responsive miRNA in hormone-refractory prostate cancer cells. For the screening of miR-29b target, we performed microarray analysis in two prostate cancer cells. Because TET2 is the primary target of miR-29 family by our analysis, we also performed TET2 signaling by microarray. In order to investigate the downsteam signals mediated by TET2 and miR-29b, we performed comprehensive analysis of gene expression in positive prostate cancer cell lines after siTET2 or miR-29b treatment. Observation of gene expression changes after treatmet with siRNA targeting TET2 or miR-29b in prostate cancer cell lines with microarray.
2015-09-01 | E-GEOD-66038 | biostudies-arrayexpress
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Project description:Tissue fibrosis is a significant health issue associated with organ dysfunction and failure. Increased deposition of collagen and other extracellular matrix (ECM) proteins in the interstitial area is a major process in the formation of tissue fibrosis. The microRNA-29 (miR-29) family has been demonstrated as anti-fibrotic microRNAs. Our recent work also showed that dysregulation of miR-29 contributes to the formation of cardiac fibrosis in animal models of uremic cardiomyopathy and replenish of miR-29 attenuated cardiac fibrosis in these animals. However, due to the multi-targeting effect, overexpression of miR-29 could result in unexpected side effect. In the current study, we constructed a novel col1a1-miR-29b vector using collagen 1a1 promoter, which can strategically express miR-29b-3p (miR-29b) in cells with high expression of collagen and thus minimize the side effect of excessive miR-29b. Because of the similarity between the col1a1 promoter in the plasmid and the endogenous col1a1 promoter in the cell, pro-fibrotic factors that stimulate endogenous collagen expression will simultaneously activate the col1a1 promoter in the plasmid vector and thus stimulate the anti-fibrotic miR-29b expression. The increased miR-29b will then contra-regulate the collagen synthesis and maintain a dynamic balance of collagen. To evaluate the anti-fibrotic effect of miR-29b overexpression, we performed RNA sequencing in MEF cells transfected with the col1a1-miR-29b vector with or without TGF-β treatment. A CMV-miR-29b vector was used as positive control. The RNA-sequencing data showed that TGF-β treatment upregulated a broad spectrum of extracellular matrix (ECM) genes. In accordance, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using GAGE package showed that the top 5 upregulated pathways after TGF-β treatment were mostly fibrosis-related, including focal adhesion, ECM reaction, and TGF-β signaling pathways, while transfection of miR-29b expression vectors attenuated the activation of these pathways, suggesting their anti-fibrotic effect. However, despite that the expression of miR-29b in CMV-miR-29b transfected cells were about 1000 times higher compared to the col1a1-miR-29b transfected cells, there was no significant difference in the anti-fibrotic effect in these cells. In summary, our work demonstrated that the col1a1-miR-29b vector expresses much lower miR-29b compared to the CMV-miR-29b vector, but it is as effective as the CMV-miR-29b vector in blocking the fibrosis-related signaling pathways in response to TGF-β treatment. Our results also suggest that miR-29b has a moderate effect on each of its targeting genes, and its anti-fibrotic effect may result from perturbation of a broad spectrum of fibrosis-related signaling pathways.
2020-12-04 | GSE158823 | GEO
Project description:We performed a microarray analysis of mouse skin treated with a miR-29b mimic or a miR-29 inhibitor in order to identify pharmacodynamic (PD) biomarkers that were reciprocally regulated in vivo in the skin
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Project description:Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes implicated in cancer and in aging due to its role as a global epigenetic modifier. TET2 has a large N-terminal domain followed by a catalytic C-terminal. Previous reports have demonstrated that the catalytic domain remains active independent of the N-terminal domain. As such, the function of the N-terminus of this large protein remains poorly characterized. Here, we identify that several isoforms of the 14-3-3 family of proteins bind TET2. 14-3-3s bind TET2 when phosphorylated at serine 99 (S99). AMPK-mediated phosphorylation at S99 promotes TET2 stability and increases global DNA 5-hydroxymethylcytosine. 14-3-3s’ interaction with TET2 serves to protect S99 phosphorylation. Disruption of this interaction leads to both reduced TET2 phosphorylation and decreased protein stability. Furthermore, we identify that the protein phosphatase 2A (PP2A) can interact with TET2 and dephosphorylates S99. Collectively, our study provides novel insights into the role of the N-terminal domain in TET2 regulation. Moreover, they demonstrate the dynamic nature of TET2 protein regulation that could have therapeutic implications for disease states resulting from reduced TET2 levels and/or activity.
2020-01-13 | PXD016160 | Pride
Project description:The goal of this study was to identify genes regulated by miRNA-29 in helper T cells. We compared gene expression in miRNA-deficient helper T cells (DGCR8-deficient) transfected with miR-29b versus control miRNA. We also compared gene expression in wildtype helper T cells transfected with miR-29 inhibitor to cells transfected with control inhibitor 3 biological replicates of each genotype (DGCR8-deficient or Wildtype C57BL/6 mice), with 2 conditions per genotype for 12 samples total. Cells from each DGCR8-deficient mouse were transfected with either miR-29b or control miRNA and cells from wildtype mice were transfected with either miR-29 inhibitors or control inhibitors
2011-07-31 | E-GEOD-30525 | biostudies-arrayexpress
Project description:Metazoan high complementarity microRNA (miRNA) binding sites can induce miRNA turnover through 3′ tailing and trimming, however the in vivo importance of this mechanism remains unknown. Here, we show that a transcript harboring a highly complementary and deeply conserved miRNA binding site for miR-29 controls zebrafish and mouse behavior. This brain-enriched transcript originated in distal vertebrates as a long noncoding RNA, which we called libra (lncRNA involved in behavioral alterations), and evolved to the protein-coding gene known as NREP in mammals where the miR-29 binding site is located within the 3′UTR. libra-deficiency results in viable fish that manifest abnormal exploration behavior. To determine if the Nrep transcript retained the regulatory noncoding function and to define the contribution of the highly complementary miR-29 binding site, we generated the NrepmiR-29scr allele in mice where the sequence of the site was scrambled to specifically uncouple Nrep function from miR-29 regulation. We show that the Nrep miR-29 binding site restricts miR-29b expression in the cerebellum. The ectopic miR-29b expression in NrepmiR-29scr mice is associated with altered cerebellum function and behavior. We finally show that the near-perfect miRNA site triggers miR-29b turnover through 3′ trimming. In summary, we demonstrate the first example of an endogenous RNA-directed miRNA degradation event in vivo that is required for normal animal behavior.
2018-01-14 | GSE98707 | GEO
Project description:Ten-eleven translocation (Tet) family-mediated DNA oxidation represents a novel epigenetic modification capable of converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) to regulate various biological processes. However, it is unknown whether the Tet family affects mesenchymal stem cells (MSCs) or the skeletal system. Here we show that depletion of Tet1 and Tet2 resulted in impaired self-renewal and differentiation of bone marrow MSCs (BMMSCs) and a significant osteopenia phenotype. Mechanistically, Tet1 and Tet2 deficiency reduced demethylation of the P2rX7 promoter and thus downregulated exosome release, leading to intracellular accumulation of miR-297a-5p, miR-297b-5p, and miR-297c-5p. These miRNAs inhibited Runx2 signaling to impair BMMSC function. We show that overexpression of P2rX7 consistently rescued the impaired BMMSCs and osteoporotic phenotype in Tet1 and Tet2 double knockout mice. These results indicate that Tet1 and Tet2 play a critical role in maintaining BMMSC and bone homeostasis through epigenetic regulation of P2rX7 to control exosome and miRNA release. This newly identified Tet/P2rX7/Runx2 cascade may serve as a target for the development of novel therapies for osteopenia disorders.
2018-04-11 | GSE108872 | GEO
Project description:The goal of this study was to identify genes regulated by miRNA-29 in helper T cells. We compared gene expression in miRNA-deficient helper T cells (DGCR8-deficient) transfected with miR-29b versus control miRNA. We also compared gene expression in wildtype helper T cells transfected with miR-29 inhibitor to cells transfected with control inhibitor
2011-08-01 | GSE30525 | GEO
Project description:Background: Global DNA methylation alterations are hallmarks of cancer. The tumor-suppressive TET enzymes, which are involved in DNA demethylation, are decreased in prostate cancer (PCa); in particular, TET2 is specifically targeted by androgen-dependent mechanisms of repression in PCa and may play a central role in carcinogenesis. Thus, identification of key genes targeted by TET2 dysregulation may provide further insight into cancer biology. Results: Using a CRISPR/Cas9-derived TET2-knockout prostate cell line, and through whole-transcriptome and whole-methylome sequencing, we identified seven candidate genes – ASB2, ETNK2, MEIS2, NRG1, NTN1, NUDT10, and SRPX – exhibiting reduced expression and increased promoter methylation, a pattern characteristic of tumor suppressors. Decreased expression of these genes significantly discriminates between recurrent and non-recurrent prostate tumors from the Cancer Genome Atlas (TCGA) cohort (n=423), and ASB2, NUDT10, and SRPX were significantly correlated with lower recurrence-free survival in patients by Kaplan-Meier analysis. ASB2, MEIS2, and SRPX also showed significantly lower expression in high-risk Gleason score 8 tumors as compared to low or intermediate risk tumors, suggesting that these genes may be particularly useful as indicators of PCa progression. Furthermore, methylation array probes in the TCGA dataset, which were proximal to the highly conserved, differentially methylated sites identified in our TET2-knockout cells, were able to significantly distinguish between matched prostate tumor and normal prostate tissues (n=50 pairs). Except ASB2, all genes exhibited significantly increased methylation at these probes, and methylation status of at least one probe for each of these genes showed association with measures of PCa progression such as recurrence, stage, or Gleason score. Since ASB2 did not have any probes within the TET2-knockout differentially methylated region, we validated ASB2 methylation in an independent series of matched tumor-normal samples (n=19) by methylation-specific qPCR, which revealed concordant and significant increases in promoter methylation within the TET2-knockout site. Conclusions: Our study identifies seven genes governed by TET2 loss in PCa which exhibit association between their methylation and expression status and measures of PCa progression. As differential methylation profiles and TET2 expression are associated with advanced PCa, further investigation of these specialized TET2 targets may provide important insights into patterns of carcinogenic gene dysregulation.
2019-04-05 | GSE128399 | GEO