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Target Directed miRNA degradation is pervasive in human cancer

ABSTRACT: How many RNA transcripts can induce degradation of microRNAs (miRNA) via the mechanism known as target-directed miRNA degradation (TDMD) is currently unknown. We developed TDMDfinder, a bioinformatics pipeline and webtool, which is based on combined sequence alignment and feature selection approaches to identify ‘high confidence’ TDMD interactions either in Human or Mouse transcriptomes. Predictions suggest that TDMD is widespread, and every miRNA is possibly under the control of endogenous targets. Experimental validations support the validity of TDMDfinder predictions with 49% accuracy, revealing novel endogenous TDMDs for miR-17, miR-19, miR-30, miR-221, miR-26 and miR-23 families. TDMD can selectively target specific miRNA family/cluster members. Features like complementarity to the miRNA 3’ region, bulge size and hybridization energy can explain the different sensitivity. A set of computational analyses performed using the multiomic TCGA platform support the involvement of TDMD in human cancer. Many TDMD transcripts showed significant anti-correlations with both miRNA levels and miRNA activity in multiple tumors and 36 highly significant Pan-cancer interactions were highlighted. A proof-of-principle TDMD-pair was experimentally dissected in breast cancer, showing that fully-functioning TDMD could impact on cancer phenotypes, such as mammosphere growth and resistance to drug treatment. Our tool unveils TDMD as a widespread mechanism and pinpoints it as new potential oncogenic mechanism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168566 | GEO | 2022/01/31

REPOSITORIES: GEO

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Target-directed microRNA degradation broadly regulates microRNA expression and embryonic growth in mammals

Project description:MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that play critical roles in development and disease. Target-directed miRNA degradation (TDMD), a pathway in which miRNAs that bind to specialized targets with extensive complementarity are rapidly decayed, has emerged as a potent mechanism of controlling miRNA levels. Nevertheless, the biological role and scope of miRNA regulation by TDMD in mammals remains poorly understood. To address these questions, we generated mice with constitutional or conditional deletion of Zswim8, which encodes an essential TDMD factor. Loss of Zswim8 resulted in major developmental defects in heart and lung, growth restriction, and perinatal lethality. Small RNA sequencing of embryonic tissues revealed widespread miRNA regulation by TDMD. Deletion of two miRNAs, miR-322 and miR-503, rescued growth of Zswim8 null embryos, directly implicating the TDMD pathway as a key regulator of mammalian body size. These data reveal the broad landscape and developmental role of TDMD in mammals.

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Project description:MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to direct widespread post-transcriptional gene repression. Although association with AGO typically protects miRNAs from nucleases, extensive pairing to some unusual target RNAs can trigger miRNA degradation. Here we found that this target-directed miRNA degradation (TDMD) required the ZSWIM8 Cullin-RING E3 ubiquitin ligase. This and other findings suggested and supported a mechanistic model of TDMD in which target-directed proteolysis of AGO by the ubiquitin–proteasome pathway exposes the miRNA for degradation. Moreover, loss-of-function studies indicated that the ZSWIM8 Cullin-RING ligase accelerates degradation of numerous miRNAs in cells of mammals, flies, and nematodes, thereby specifying the half-lives of most short-lived miRNAs. These results elucidate the mechanism of TDMD and expand the inferred role of TDMD in shaping miRNA levels in bilaterian animals.

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Structural Basis for Target-Directed MicroRNA Degradation

Project description:We used HSUR1 – a small non-coding RNA from Herpesvirus saimiri that induces degradation of host miR-27 – to validate structural insights into target-directed miRNA degradation (TDMD). While performing systematic mutagenesis of HSUR1 we noticed that HSUR1 mutants exhibiting complementarity to the extreme 3' end of miR-27, lead to generation of extended miR-27 isoforms (isomiRs). These isomiRs likely represent failed products of TDMD and could mean that features of the pairing between the TDMD target and miRNA dictate which enzymes are recruited to modify the miRNA 3′ end. Small RNA sequencing revealed that a mixture of adenylates and uridylates is added to the 3′ end of miR-27 during TDMD.

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Endogenous transcripts control miRNA levels and activity in mammalian cells by a target-dependent miRNA degradation mechanism [RNA-Seq]

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.

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