Oncogenic role of the non-canonical base-pairing between miRNAs/mRNAs in uveal melanoma.
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PROVIDER: PRJNA748059 | ENA |
REPOSITORIES: ENA
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Project description:Chromosome 3p monosomy is associated with a poor clinical outcome of patients with uveal melanoma. Since a copy of the tumor suppressor miR-16 gene is lost for these patients, we postulated that a 3p loss may reduce the miR-16 amount and activity, promoting RNA derepression and tumor burden (loss of brake effect) as observed in chronic lymphocytic leukemia. Unexpectedly, we found that miR-16 expression level is not decreased despite the 3p monosomy. In contrast, our results suggested that miR-16 activity is impaired in uveal melanoma. Here, we investigated the molecular mechanism explaining the sequestration of miR-16 by RNAs. By defining the miR-16 interactome, two genes sets have been highlighted, suggesting two divergent miR-16 functions. In addition to the canonical miR-16 targets such as CCND3 and CDC25A, we identified another set of miR-16-interacting RNAs called thereafter miR-16 sponges. miR-16 binds to these RNAs sponge without inducing their decay. Mechanistically, the miR-16/RNA non-canonical base-pairing promoted stability of mRNAs involved in cancer cell proliferation. The biological relevance has been challenged in uveal melanoma. We showed that patients with poor overall survival expressed higher levels of miR-16 sponges and canonical miR-16 targets. These results strongly suggested that miR-16 is no longer able to repress its targets and, in contrast, promotes RNA stability and protein expression of oncogenes. miR-16 activity assessment using our Sponge-signature discriminates the patient’s overall survival as efficiently as the current method based on copy number variations and driver mutations detection. To conclude, miRNA loss of function due miRNA sequestration seems to promote cancer burden by two combined events – “loss of brake and an acceleration”. Our results highlight the oncogenic role of the non-canonical base-pairing between miRNAs/mRNAs in uveal melanoma.
2022-10-05 | GSE180399 | GEO
Project description:Chromosome 3p monosomy is associated with a poor clinical outcome of patients with uveal melanoma. Since a copy of the tumor suppressor miR-16 gene is lost for these patients, we postulated that a 3p loss may reduce the miR-16 amount and activity, promoting RNA derepression and tumor burden (loss of brake effect) as observed in chronic lymphocytic leukemia. Unexpectedly, we found that miR-16 expression level is not decreased despite the 3p monosomy. In contrast, our results suggested that miR-16 activity is impaired in uveal melanoma. Here, we investigated the molecular mechanism explaining the sequestration of miR-16 by RNAs. By defining the miR-16 interactome, two genes sets have been highlighted, suggesting two divergent miR-16 functions. In addition to the canonical miR-16 targets such as CCND3 and CDC25A, we identified another set of miR-16-interacting RNAs called thereafter miR-16 sponges. miR-16 binds to these RNAs sponge without inducing their decay. Mechanistically, the miR-16/RNA non-canonical base-pairing promoted stability of mRNAs involved in cancer cell proliferation. The biological relevance has been challenged in uveal melanoma. We showed that patients with poor overall survival expressed higher levels of miR-16 sponges and canonical miR-16 targets. These results strongly suggested that miR-16 is no longer able to repress its targets and, in contrast, promotes RNA stability and protein expression of oncogenes. miR-16 activity assessment using our Sponge-signature discriminates the patient’s overall survival as efficiently as the current method based on copy number variations and driver mutations detection. To conclude, miRNA loss of function due to miRNA sequestration seems to promote cancer burden by two combined events – 'loss of brake and an acceleration'. Our results highlight the oncogenic role of the non-canonical base-pairing between miRNAs/mRNAs in uveal melanoma.
2022-10-04 | E-MTAB-10940 | biostudies-arrayexpress
Project description:Viral miRNA adaptor differentially recruits miRNAs to target mRNAs through alternative base-pairing
| PRJNA515932 | ENA
Project description:HSUR2 is a viral non-coding RNA (ncRNA) that functions as a microRNA (miRNA) adaptor. HSUR2 inhibits apoptosis in infected cells by recruiting host miRNAs miR-142-3p and miR-16 to mRNAs encoding apoptotic factors. HSUR2's target recognition mechanism is not understood. It is also unknown why HSUR2 utilizes miR-16 to downregulate only a subset of transcripts. We developed a general method for individual-nucleotide resolution RNA-RNA interaction identification by crosslinking and capture (iRICC) to identify sequences mediating interactions between HSUR2 and target mRNAs in vivo. Mutational analyses confirmed identified HSUR2-mRNA interactions and validated iRICC as a method that confidently determines sequences mediating RNA-RNA interactions in vivo. We show that HSUR2 does not display a 'seed' region to base-pair with most target mRNAs, but instead uses different regions to interact with different transcripts. We further demonstrate that this versatile mode of interaction via variable base-pairing provides HSUR2 with a mechanism for differential miRNA recruitment.
| S-EPMC6763288 | biostudies-literature
Project description:Here we describe a new class of immunostimulatory short duplex RNAs that potently induce production of type I interferon (IFN-I), and particularly IFN-β, in a wide range ofhuman cell types via end-to-end dimerization, direct binding to RIG-I, and activation of the RIG-I/IRF3 pathway. These RNAs require a minimum of 20 base pairs, lack any sequence or structural characteristics of known immunostimulatory RNAs, and instead require a unique conserved sequence motif (sense strand: 5’-C, antisense strand: 3’-GGG) that mediates the self-assembly of end-to-end RNA dimers by Hoogsteen G-G base-pairing. The presence of terminal hydroxyl or monophosphate groups, blunt or overhanging ends, or terminal RNA or DNA bases also did not affect their ability to induce IFN-I production. Immune stimulation mediated by these duplex RNAs results in broad spectrum inhibition of infections by many respiratory viruses with pandemic potential, including SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A, as well as the common cold virus HCoV-NL63 in cell lines and in human Lung Chips that mimic organlevel lung pathophysiology. These novel immunostimulatory motifs potentially could be harnessed to create broad-spectrum antiviral therapeutics, but they should be avoided when designing siRNAs to minimize immunological side effects.
2022-09-01 | PXD027838 | Pride
Project description:The viral non-coding RNA HSUR2 regulates apoptosis by recruiting host microRNAs to host mRNAs encoding apoptotic factors. The mechanism whereby HSUR2 targets specific host mRNAs is unknown. Here we developed iRICC to identify sequences mediating RNA-RNA interactions in vivo between a single RNA of interest and its binding RNAs. Sequences that mediate HSUR2-mRNA interactions identified by iRICC-seq were functionally validated by mutational analyses. Unlike other small regulatory non-coding RNAs, HSUR2 does not contain a “seed” region responsible for interaction with most target mRNAs, but rather uses different sequences to bind to different targets. Our findings describe a mode of interaction that provides HSUR2 with flexibility both in target recognition and in the selection of trans-acting miRNAs that are recruited for target mRNA repression.
2019-09-27 | GSE125371 | GEO
Project description:Bacteria selectively consume some carbon sources over others through a regulatory mechanism termed catabolite repression. Here, we show that the base pairing RNA Spot 42 plays a broad role in catabolite repression in Escherichia coli by directly repressing genes involved in central and secondary metabolism, redox balancing, and the consumption of diverse non-preferred carbon sources. Many of the genes repressed by Spot 42 are transcriptionally activated by the global regulator CRP. Since CRP represses Spot 42, these regulators participate in a specific regulatory circuit called a multi-output feedforward loop. We found that this loop can reduce leaky expression of target genes in the presence of glucose and can maintain repression of target genes under changing nutrient conditions. Our results suggest that base pairing RNAs in feedforward loops can help shape the steady-state levels and dynamics of gene expression.
2011-01-01 | GSE24875 | GEO
Project description:Bacteria selectively consume some carbon sources over others through a regulatory mechanism termed catabolite repression. Here, we show that the base pairing RNA Spot 42 plays a broad role in catabolite repression in Escherichia coli by directly repressing genes involved in central and secondary metabolism, redox balancing, and the consumption of diverse non-preferred carbon sources. Many of the genes repressed by Spot 42 are transcriptionally activated by the global regulator CRP. Since CRP represses Spot 42, these regulators participate in a specific regulatory circuit called a multi-output feedforward loop. We found that this loop can reduce leaky expression of target genes in the presence of glucose and can maintain repression of target genes under changing nutrient conditions. Our results suggest that base pairing RNAs in feedforward loops can help shape the steady-state levels and dynamics of gene expression. MG1655 lacIq cells harboring the control vector pBRplac or the Spot 42-inducible vector pSpot42 were grown in LB to an ABS600 of ~0.4 and treated with 1 mM IPTG. After 7 min, total RNA was isolated using the hot phenol extraction procedure.
2011-01-01 | E-GEOD-24875 | biostudies-arrayexpress
Project description:The problem of systematic and objective identification of canonical and non-canonical base pairs in RNA three-dimensional (3D) structures was studied. A probabilistic approach was applied, and an algorithm and its implementation in a computer program that detects and analyzes all the base pairs contained in RNA 3D structures were developed. The algorithm objectively distinguishes among canonical and non-canonical base pairing types formed by three, two and one hydrogen bonds (H-bonds), as well as those containing bifurcated and C-H.X...H-bonds. The nodes of a bipartite graph are used to encode the donor and acceptor atoms of a 3D structure. The capacities of the edges correspond to probabilities computed from the geometry of the donor and acceptor groups to form H-bonds. The maximum flow from donors to acceptors directly identifies base pairs and their types. A complete repertoire of base pairing types was built from the detected H-bonds of all X-ray crystal structures of a resolution of 3.0 A or better, including the large and small ribosomal subunits. The base pairing types are labeled using an extension of the nomenclature recently introduced by Leontis and Westhof. The probabilistic method was implemented in MC-Annotate, an RNA structure analysis computer program used to determine the base pairing parameters of the 3D modeling system MC-Sym.
| S-EPMC140540 | biostudies-literature
Project description:In vivo-like nearest neighbor parameters accurately predict fractional RNA base-pairing in cells
| PRJNA976738 | ENA