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 | 2026/06/30
REPOSITORIES: GEO
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Project description:MicroRNAs (miRNAs) play pivotal roles in cancer biology and hold promise as therapeutic targets. A recently discovered mechanism, termed target-directed miRNA degradation (TDMD), involves certain RNA transcripts ("triggers") inducing the degradation of miRNAs ("substrates"). The extent of TDMD regulation in human cancer and its implications in cancer phenotypes remain poorly understood. Here, we fill this gap identifying miRNA substrates that accumulate post-transcriptionally upon TDMD blockade in a panel of breast cancer cell lines. Our approach identified 31 high-confidence miRNA substrates, with a few miRNAs - including miR-7, miR-29b and miR-33a/b - controlled by degradation in multiple cell types. Combining transcriptome-wide mapping of miRNA:mRNA interactions by eCLIP with single cell RNA sequencing analysis of intratumor heterogeneity, we found that NREP limits the expression and activity of miR-29b in triple-negative breast cancer (TNBC) cell lines, fine tuning the transcriptional and phenotypic plasticity of cells along the epithelial-to-mesenchymal trajectory. Lastly, we demonstrated the existence of a non-canonical TDMD mechanism. Specifically, SERPINE1 triggers miR-30c-5p degradation in a ZSWIM8-independent manner in TNBC cell lines, contributing to aggressive cancer phenotypes such as cancer stem cell behavior, drug resistance, and cancer heterogeneity. In conclusion, our findings support a direct role for the TDMD mechanism in cancer biology and suggest a broader involvement of miRNA decay in human physiopathology.
2026-06-30 | GSE263552 | GEO
Project description:MicroRNAs (miRNAs) play pivotal roles in cancer biology and hold promise as therapeutic targets. A recently discovered mechanism, termed target-directed miRNA degradation (TDMD), involves certain RNA transcripts ("triggers") inducing the degradation of miRNAs ("substrates"). The extent of TDMD regulation in human cancer and its implications in cancer phenotypes remain poorly understood. Here, we fill this gap identifying miRNA substrates that accumulate post-transcriptionally upon TDMD blockade in a panel of breast cancer cell lines. Our approach identified 31 high-confidence miRNA substrates, with a few miRNAs - including miR-7, miR-29b and miR-33a/b - controlled by degradation in multiple cell types. Combining transcriptome-wide mapping of miRNA:mRNA interactions by eCLIP with single cell RNA sequencing analysis of intratumor heterogeneity, we found that NREP limits the expression and activity of miR-29b in triple-negative breast cancer (TNBC) cell lines, fine tuning the transcriptional and phenotypic plasticity of cells along the epithelial-to-mesenchymal trajectory. Lastly, we demonstrated the existence of a non-canonical TDMD mechanism. Specifically, SERPINE1 triggers miR-30c-5p degradation in a ZSWIM8-independent manner in TNBC cell lines, contributing to aggressive cancer phenotypes such as cancer stem cell behavior, drug resistance, and cancer heterogeneity. In conclusion, our findings support a direct role for the TDMD mechanism in cancer biology and suggest a broader involvement of miRNA decay in human physiopathology.
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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
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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 | GSE112578 | 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 | GSE104598 | GEO
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2016-05-06 | PXD003938 | Pride
Project description:Precise control of microRNA (miRNA) expression is critical for normal development. An important mechanism of miRNA regulation is target-directed microRNA degradation (TDMD), a pathway in which the binding of miRNAs to specialized trigger RNAs induces ubiquitylation and decay of associated Argonaute (AGO) proteins by the ZSWIM8 ubiquitin ligase. ZSWIM8-deficient mice exhibit reduced body size, cardiopulmonary and neurodevelopmental defects, and perinatal lethality. Despite widespread dysregulation of miRNAs in these animals, the vast majority of presumptive trigger RNAs that induce decay of ZSWIM8-regulated miRNAs remain undefined. Here, using AGO crosslinking and sequencing of hybrids (AGO-CLASH), a high-throughput method for identifying miRNA binding sites, we report the identification of Plagl1 as a trigger for TDMD of miR-322-5p, and Lrrc58 and Malat1 as TDMD triggers for miR-503-5p in mouse embryonic fibroblasts (MEFs). In mice, deletion of the miR-322-5p and miR-503-5p trigger sites in the Plagl1 and Lrrc58 3' UTRs, respectively, abrogated TDMD of these miRNAs and resulted in miR-322/503-dependent embryonic growth restriction, recapitulating a key feature of the Zswim8—/— phenotype. Thus, these results demonstrate that the transcripts encoding Plagl1 and Lrrc58 regulate mammalian body size by inducing degradation of miR-322-5p and miR-503-5p and provide a valuable resource for identification of additional TDMD triggers.
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Project description:Precise control of microRNA (miRNA) expression is critical for normal development. An important mechanism of miRNA regulation is target-directed microRNA degradation (TDMD), a pathway in which the binding of miRNAs to specialized trigger RNAs induces ubiquitylation and decay of associated Argonaute (AGO) proteins by the ZSWIM8 ubiquitin ligase. ZSWIM8-deficient mice exhibit reduced body size, cardiopulmonary and neurodevelopmental defects, and perinatal lethality. Despite widespread dysregulation of miRNAs in these animals, the vast majority of presumptive trigger RNAs that induce decay of ZSWIM8-regulated miRNAs remain undefined. Here, using AGO crosslinking and sequencing of hybrids (AGO-CLASH), a high-throughput method for identifying miRNA binding sites, we report the identification of Plagl1 as a trigger for TDMD of miR-322-5p, and Lrrc58 and Malat1 as TDMD triggers for miR-503-5p in mouse embryonic fibroblasts (MEFs). In mice, deletion of the miR-322-5p and miR-503-5p trigger sites in the Plagl1 and Lrrc58 3' UTRs, respectively, abrogated TDMD of these miRNAs and resulted in miR-322/503-dependent embryonic growth restriction, recapitulating a key feature of the Zswim8—/— phenotype. Thus, these results demonstrate that the transcripts encoding Plagl1 and Lrrc58 regulate mammalian body size by inducing degradation of miR-322-5p and miR-503-5p and provide a valuable resource for identification of additional TDMD triggers.
2025-11-11 | GSE299946 | GEO