RNA-seq gene expression profile of SUM159PT breast cancer cell line upon manipulation of two TDMD triggers, NREP and SERPINE1
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE236783 | GEO | 2024/12/31
REPOSITORIES: GEO
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Project description:RNA-seq gene expression profile of SUM159PT breast cancer cell line upon manipulation of two TDMD triggers, NREP and SERPINE1
| PRJNA992422 | ENA
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:Little is known about how miRNAs are turned over, in particular in mammalian cells. A target-dependent miRNA degradation mechanism (TDMD) has been recently suggested, in which RNA targets may induce miRNA degradation. However, endogenous RNA targets involved in TDMD have not been yet identified. During serum stimulation of quiescent fibroblasts, a deep change of miRNA expression occurs in few hours. We scanned the mammalian genome for targets eligible for TDMD and found a dominant miRNA:target pair, consisting of a target (SerpinE1) extraordinarily induced upon serum stimulation and two matched miRNAs (miR-30b/c) quickly downregulated. We verified directly the occurrence of TDMD by interfering specifically with the miR-:target interaction, keeping target and miRNA expression at endogenous levels, using CRISPR/cas9 mediated deletion of the miR-30 responsive element (MRE) of SerpinE1. In MRE-KO cells, we observed the stabilization of the predicted miRNAs, with no evidence of alterations in precursors or unrelated miRNAs, suggesting that TDMD is occurring and has been disrupted by a single MRE deletion. At molecular level miRNA degradation occurs within physiological ranges of target expression (upon 1000 copies per cells) and is accompanied by modification on 3’ends (tailing, mostly through adenylation). TDMD suppression was sufficient to shift the activity of miR-30b/c towards other shared targets, modulate significantly gene expression and, thus, influence cellular functions, including cell proliferation, apoptosis, and adhesion. In conclusion, these data strongly support the existence of a novel and sophisticated regulatory layer of miRNA and gene expression mediated by specific endogenous targets in mammalian cells.
2018-06-26 | GSE104598 | GEO
Project description:Little is known about how miRNAs are turned over, in particular in mammalian cells. A target-dependent miRNA degradation mechanism (TDMD) has been recently suggested, in which RNA targets may induce miRNA degradation. However, endogenous RNA targets involved in TDMD have not been yet identified. During serum stimulation of quiescent fibroblasts, a deep change of miRNA expression occurs in few hours. We scanned the mammalian genome for targets eligible for TDMD and found a dominant miRNA:target pair, consisting of a target (SerpinE1) extraordinarily induced upon serum stimulation and two matched miRNAs (miR-30b/c) quickly downregulated. We verified directly the occurrence of TDMD by interfering specifically with the miR-:target interaction, keeping target and miRNA expression at endogenous levels, using CRISPR/cas9 mediated deletion of the miR-30 responsive element (MRE) of SerpinE1. In MRE-KO cells, we observed the stabilization of the predicted miRNAs, with no evidence of alterations in precursors or unrelated miRNAs, suggesting that TDMD is occurring and has been disrupted by a single MRE deletion. At molecular level miRNA degradation occurs within physiological ranges of target expression (upon 1000 copies per cells) and is accompanied by modification on 3’ends (tailing, mostly through adenylation). TDMD suppression was sufficient to shift the activity of miR-30b/c towards other shared targets, modulate significantly gene expression and, thus, influence cellular functions, including cell proliferation, apoptosis, and adhesion. In conclusion, these data strongly support the existence of a novel and sophisticated regulatory layer of miRNA and gene expression mediated by specific endogenous targets in mammalian cells.
2018-06-26 | GSE104648 | GEO
Project description:Little is known about how miRNAs are turned over, in particular in mammalian cells. A target-dependent miRNA degradation mechanism (TDMD) has been recently suggested, in which RNA targets may induce miRNA degradation. However, endogenous RNA targets involved in TDMD have not been yet identified. During serum stimulation of quiescent fibroblasts, a deep change of miRNA expression occurs in few hours. We scanned the mammalian genome for targets eligible for TDMD and found a dominant miRNA:target pair, consisting of a target (SerpinE1) extraordinarily induced upon serum stimulation and two matched miRNAs (miR-30b/c) quickly downregulated. We verified directly the occurrence of TDMD by interfering specifically with the miR-:target interaction, keeping target and miRNA expression at endogenous levels, using CRISPR/cas9 mediated deletion of the miR-30 responsive element (MRE) of SerpinE1. In MRE-KO cells, we observed the stabilization of the predicted miRNAs, with no evidence of alterations in precursors or unrelated miRNAs, suggesting that TDMD is occurring and has been disrupted by a single MRE deletion. At molecular level miRNA degradation occurs within physiological ranges of target expression (upon 1000 copies per cells) and is accompanied by modification on 3’ends (tailing, mostly through adenylation). TDMD suppression was sufficient to shift the activity of miR-30b/c towards other shared targets, modulate significantly gene expression and, thus, influence cellular functions, including cell proliferation, apoptosis, and adhesion. In conclusion, these data strongly support the existence of a novel and sophisticated regulatory layer of miRNA and gene expression mediated by specific endogenous targets in mammalian cells.
2018-06-26 | GSE112578 | GEO
Project description:Overexpression and inhibition of miR-29 (pre-miR and anti-miR to miR-29b) in murine aortic smooth muscle cells, analysis of their secretome (conditioned media after serum starvation), n=3 for all four groups (pre-miR control, pre-miR-29b, anti-miR control, anti-miR-29b).
2016-05-06 | PXD003938 | Pride
Project description:Binding of microRNAs (miRNA) to mRNAs normally results in post-transcriptional repression. However, extensive base-pairing between miRNAs and target RNAs can trigger miRNA degradation, a phenomenon called target RNA-directed miRNA degradation (TDMD). Here, we systematically analyzed Argonaute-CLASH (crosslinking, ligation, and sequencing of miRNA-target RNA hybrids) data, and identified numerous candidate TDMD triggers based on their ability to induce non-templated nucleotide addition at the miRNA 3 end. When overexpressed in HEK293T cells, nine highly conserved triggers induce degradation of corresponding miRNAs. Consistent with previous reports, both the TDMD base-pairing and surrounding sequences are important for TDMD. CRISPR knockout of endogenous trigger or ZSWIM8, a ubiquitin ligase essential for TDMD, reduce miRNA degradation. Furthermore, degradation of miR-221 and miR-222 by a trigger in BCL2L11, which encodes an apoptotic protein, enhances apoptosis. Therefore, we uncovered widespread TDMD triggers in target RNAs and demonstrated that they can functionally cooperate with the encoded proteins.
2024-06-25 | GSE178943 | GEO
Project description:The clinical outcomes of hepatocellular carcinoma (HCC) remain dismal. Elucidating the molecular mechanisms for the progression of aggressive HCC holds the promise for developing novel intervention strategies. The transactivation response element RNA-binding protein (TRBP/TARBP2), a key component of microRNA (miRNA) processing and maturation machinery has exhibited to play conflicting roles in tumor development and progression. We sought to investigate the expression of TARBP2 in HCC using well-characterized HCC cell lines, patient-derived tissues and blood samples. Additionally, the potential prognostic and diagnostic value of TARBP2 in HCC were analyzed using Kaplan-Meier plots and ROC curve. Cell counting kit‐8 (CCK‐8), wound healing and transwell assays examined the ability of TARBP2 to induce cell proliferation, migration, and invasion in HCC cell lines. RNA sequencing was applied to identify the downstream elements of TARBP2. The interaction of potential targets of TARBP2, miR‐145 and serpin family E member 1 (SERPINE1), was assessed using luciferase reporter assay. TARBP2 expression was down-regulated in HCC cell lines relative to normal hepatocyte cells, with a similar pattern further confirmed in tissue and blood samples. Notably, the loss of TARBP2 was demonstrated to promote proliferation, migration, and invasion in HCC cell lines. Interestingly, the reduction of TARBP2 was shown to result in the upregulation of SERPINE1, also known as plasminogen activator inhibitor (PAI-1), which is a vital gene of the HIF-1 signaling pathway. Knockdown of SERPINE1 rescued the TARBP2-lost phenotype. Moreover, TARBP2 depletion induced the upregulation of SERPINE1 through reducing the processing of miR-145, which directly targets SERPINE1. Finally, overexpression of miR-145 repressed SERPINE1 and rescued the functions in sh-TARBP2 HCC cells. Our findings underscore a linear TARBP2-miR-145-SERPINE1 pathway that drives HCC progression, with the potential as a novel intervention target for aggressive HCC.
2021-05-26 | GSE143551 | GEO
Project description:Serpine1 mRNA is abundantly induced during EMT. Paradoxically, this mRNA is enriched in the RISC complex, blocking its translation and acting as an endogenous RNA competitor for several miRNAs. Cells that overexpress Serpine1 mRNA have a greater capacity for migration, invasiveness, and resistance to anoikis. These cells show an altered proteomic profile, highlighting the increased levels of expression of the splicing factor TRA2b. This splicing factor is posttranscriptionally regulated during EMT by upregulation of Serpine1 mRNA and the resulting sequestration of miR-130b-5p by this mRNA, which contains three binding sites for miR-130b-5p. Through transcriptomic analysis, we confirmed that Serpin 1 mRNA expression modulates the expression of numerous genes, most of which (>60%) are also modulated by TRA2b overexpression.
2023-12-15 | GSE221152 | GEO
Project description:Serpine1 mRNA is abundantly induced during EMT. Paradoxically, this mRNA is enriched in the RISC complex, blocking its translation and acting as an endogenous RNA competitor for several miRNAs. Cells that overexpress Serpine1 mRNA have a greater capacity for migration, invasiveness, and resistance to anoikis. These cells show an altered proteomic profile, highlighting the increased levels of expression of the splicing factor TRA2b. This splicing factor is posttranscriptionally regulated during EMT by upregulation of Serpine1 mRNA and the resulting sequestration of miR-130b-5p by this mRNA, which contains three binding sites for miR-130b-5p. Through transcriptomic analysis, we confirmed that Serpin 1 mRNA expression modulates the expression of numerous genes, most of which (>60%) are also modulated by TRA2b overexpression.
2023-12-15 | GSE221076 | GEO