Description of plant tRNA-derived RNA fragments (tRFs) associated with argonaute and identification of their putative targets.
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ABSTRACT:
SUBMITTER: Loss-Morais G
PROVIDER: S-EPMC3574835 | biostudies-other | 2013
REPOSITORIES: biostudies-other
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Project description:BackgroundtRNA-derived fragments (tRFs) are 14-40-nucleotide-long, small non-coding RNAs derived from specific tRNA cleavage events with key regulatory functions in many biological processes. Many studies have shown that tRFs are associated with Argonaute (AGO) complexes and inhibit gene expression in the same manner as miRNAs. However, there are currently no tools for accurately predicting tRF target genes.MethodsWe used tRF-mRNA pairs identified by crosslinking, ligation, and sequencing of hybrids (CLASH) and covalent ligation of endogenous AGO-bound RNAs (CLEAR)-CLIP to assess features that may participate in tRF targeting, including the sequence context of each site and tRF-mRNA interactions. We applied genetic algorithm (GA) to select key features and support vector machine (SVM) to construct tRF prediction models.ResultsWe first identified features that globally influenced tRF targeting. Among these features, the most significant were the minimum free folding energy (MFE), position 8 match, number of bases paired in the tRF-mRNA duplex, and length of the tRF, which were consistent with previous findings. Our constructed model yielded an area under the receiver operating characteristic (ROC) curve (AUC) = 0.980 (0.977-0.983) in the training process and an AUC = 0.847 (0.83-0.861) in the test process. The model was applied to all the sites with perfect Watson-Crick complementarity to the seed in the 3' untranslated region (3'-UTR) of the human genome. Seven of nine target/nontarget genes of tRFs confirmed by reporter assay were predicted. We also validated the predictions via quantitative real-time PCR (qRT-PCR). Thirteen potential target genes from the top of the predictions were significantly down-regulated at the mRNA levels by overexpression of the tRFs (tRF-3001a, tRF-3003a or tRF-3009a).ConclusionsPredictions can be obtained online, tRFTars, freely available at http://trftars.cmuzhenninglab.org:3838/tar/ , which is the first tool to predict targets of tRFs in humans with a user-friendly interface.
| S-EPMC7908658 | biostudies-literature
Project description:Transfer RNA fragments (tRFs) are an emerging class of small RNA molecules derived from mature or precursor tRNAs. They are found across a wide range of organisms and tissues, in small RNA fraction or loaded to Argonaute in numbers comparable to microRNAs. Their functions and mechanisms of action are largely unknown, and results obtained on individual tRFs are often hard to generalize. Here we predicted binding mechanisms and specific target interaction sites of 26 human Argonaute-loaded tRFs of different types using large-scale meta-analyses of available experimental data. Strikingly, our findings matched all interaction sites detected in a recent experimental screen, confirming the validity of our computational approach. Such sites are primarily located on the 5' end of tRFs and often involve additional binding along the tRF length, similar to microRNAs. Indicative of multiple layers of regulation, diverse regulatory non-coding RNAs comprised a third of the tRF targets, with the rest being protein-coding transcripts. In the latter, coding sequence and 3' UTRs were the likely primary target regions, although we observed interactions of tRFs with 5' UTRs. Another novel phenomenon we report, a large number of putative interactions between tRFs and introns, is compatible with the roles of Argonaute in the nucleus. Further, observed tRF-intron binding modes suggest a mechanism of interaction of tRFs with Argonaute-dependent introns, and we predict here >20 candidate introns of this type. Taken together, these results present tRFs as regulatory molecules with a rich functional spectrum.
| S-EPMC7549686 | biostudies-literature
Project description:The discovery of small noncoding RNAs (sncRNAs) with regulatory functions is a recent breakthrough in biology. Among sncRNAs, microRNA (miRNA), derived from host or virus, has emerged as elements with high importance in control of viral replication and host responses. However, the expression pattern and functional aspects of other types of sncRNAs, following viral infection, are unexplored. In order to define expression patterns of sncRNAs, as well as to discover novel regulatory sncRNAs in response to viral infection, we applied deep sequencing to cells infected with human respiratory syncytial virus (RSV), the most common cause of bronchiolitis and pneumonia in babies. RSV infection leads to abundant production of transfer RNA (tRNA)-derived RNA Fragments (tRFs) that are ~30 nucleotides (nts) long and correspond to the 5'-half of mature tRNAs. At least one tRF, which is derived from tRNA-Glu-CTC, represses target mRNA in the cytoplasm and promotes RSV replication. This demonstrates that this tRF is not a random by-product of tRNA degradation but a functional molecule. The biogenesis of this tRF is also specific, as it is mediated by the endonuclease angiogenin (ANG), not by other nucleases. In summary, our study presents novel information on the induction of a functional tRF by viral infection.
| S-EPMC3594034 | biostudies-literature
Project description:BackgroundDevelopment of sequencing technologies and supporting computation enable discovery of small RNA molecules that previously escaped detection or were ignored due to low count numbers. While the focus in the analysis of small RNA libraries has been primarily on microRNAs (miRNAs), recent studies have reported findings of fragments of transfer RNAs (tRFs) across a range of organisms.ResultsHere we describe Drosophila melanogaster tRFs, which appear to have a number of structural and functional features similar to those of miRNAs but are less abundant. As is the case with miRNAs, (i) tRFs seem to have distinct isoforms preferentially originating from 5' or 3' end of a precursor molecule (in this case, tRNA), (ii) ends of tRFs appear to contain short "seed" sequences matching conserved regions across 12 Drosophila genomes, preferentially in 3' UTRs but also in introns and exons; (iii) tRFs display specific isoform loading into Ago1 and Ago2 and thus likely function in RISC complexes; (iii) levels of loading in Ago1 and Ago2 differ considerably; and (iv) both tRF expression and loading appear to be age-dependent, indicating potential regulatory changes from young to adult organisms.ConclusionsWe found that Drosophila tRF reads mapped to both nuclear and mitochondrial tRNA genes for all 20 amino acids, while previous studies have usually reported fragments from only a few tRNAs. These tRFs show a number of similarities with miRNAs, including seed sequences. Based on complementarity with conserved Drosophila regions we identified such seed sequences and their possible targets with matches in the 3'UTR regions. Strikingly, the potential target genes of the most abundant tRFs show significant Gene Ontology enrichment in development and neuronal function. The latter suggests that involvement of tRFs in the RNA interfering pathway may play a role in brain activity or brain changes with age.
| S-EPMC4572633 | biostudies-literature
Project description: Not available
| S-EPMC6935952 | biostudies-literature
Project description:Transfer RNA-derived fragments (tRFs) represent a novel class of small RNAs (sRNAs) generated through endonucleolytic cleavage of both mature and precursor transfer RNAs (tRNAs). These 14-28 nt length tRFs that have been extensively studied in animal kingdom are to be explored in plants. In this study, we introduce a database of plant tRFs named PtRFdb (www.nipgr.res.in/PtRFdb), for the scientific community. We analyzed a total of 1344 sRNA sequencing datasets of 10 different plant species and identified a total of 5607 unique tRFs (758 tRF-1, 2269 tRF-3 and 2580 tRF-5), represented by 487 765 entries. In PtRFdb, detailed and comprehensive information is available for each tRF entry. Apart from the core information consisting of the tRF type, anticodon, source organism, tissue, sequence and the genomic location; additional information like PubMed identifier (PMID), Sample accession number (GSM), sequence length and frequency relevant to the tRFs may be of high utility to the user. Two different types of search modules (Basic Search and Advanced Search), sequence similarity search (by BLAST) and Browse option with data download facility for each search is provided in this database. We believe that PtRFdb is a unique database of its kind and it will be beneficial in the validation and further characterization of plant tRFs.Database URL: http://www.nipgr.res.in/PtRFdb/.
| S-EPMC6016605 | biostudies-literature
Project description:tRFs, 14 to 32 nt long single-stranded RNA derived from mature or precursor tRNAs, are a recently discovered class of small RNA that have been found to be present in diverse organisms at read counts comparable to miRNAs. Currently, there is a debate about their biogenesis and function.This is the first meta-analysis of tRFs. Analysis of more than 50 short RNA libraries has revealed that tRFs are precisely generated fragments present in all domains of life (bacteria to humans), and are not produced by the miRNA biogenesis pathway. Human PAR-CLIP data shows a striking preference for tRF-5s and tRF-3s to associate with AGO1, 3 and 4 rather than AGO2, and analysis of positional T to C mutational frequency indicates these tRFs associate with Argonautes in a manner similar to miRNAs. The reverse complements of canonical seed positions in these sequences match cross-link centered regions, suggesting these tRF-5s and tRF-3s interact with RNAs in the cell. Consistent with these results, human AGO1 CLASH data contains thousands of tRF-5 and tRF-3 reads chimeric with mRNAs.tRFs are an abundant class of small RNA present in all domains of life whose biogenesis is distinct from miRNAs. In human HEK293 cells tRFs associate with Argonautes 1, 3 and 4 and not Argonaute 2 which is the main effector protein of miRNA function, but otherwise have very similar properties to miRNAs, indicating tRFs may play a major role in RNA silencing.
| S-EPMC4203973 | biostudies-literature
Project description:Transfer RNA-derived fragments (tRFs) are known to contribute to multiple illnesses, including cancers, viral infections, and age-related neurodegeneration. In this study, we used senescence-accelerated mouse prone 8 (SAMP8) as a model of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, and a control, the senescence-accelerated mouse resistant 1 (SAMR1) model, to comprehensively explore differences in tRF expression between them. We discovered 570 tRF transcripts among which eight were differentially expressed. We then obtained 110 potential target genes in a miRNA-like pattern. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation suggest that these target genes participate in a variety of brain functions; e.g., synapse formation (GO: 0045202) and the synaptic vesicle cycle pathway. We further assessed in detail those tRFs whose miRNA-like pattern was most likely to promote the progression of either Alzheimer's or Parkinson's disease, such as AS-tDR-011775 acting on Mobp and Park2. Our findings suggest the eight dysregulated tRFs we uncovered here may be beneficially exploited as potential diagnostic biomarkers and/or therapeutic targets to treat age-related brain diseases.
| S-EPMC6914438 | biostudies-literature
Project description:In this article, we report a small RNA data set obtained from human T cell acute leukemia Jurkat cells, which were treated with the universal apoptotic agent camptothecin. Based on the Annexin-V labeling pattern, we sorted two Jurkat subpopulations in treated cells: one that is sensitive to the drug and the other being relatively more resistant. We report new original data that include the frequency of tRNA-derived fragments (tRF) in drug-sensitive and resistant cells. We also present partially analyzed data to show the origin of reads on tRNAs as well as the borders of the fragments. We believe that this data can benefit the science community working in the field of tRF and/or apoptosis.
| S-EPMC5988338 | biostudies-literature
Project description:The tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs) are newly discovered noncoding RNAs in recent years. They are derived from specific cleavage of mature and pre-tRNAs and expressed in various cancers. They enhance cell proliferation and metastasis or inhibit cancer progression. Many studies have investigated their roles in the diagnosis, progression, metastasis, and prognosis of various cancers, but the mechanisms through which they are involved in resistance to cancer treatment are unclear. This review outlines the classification of tRFs and tiRNAs and their mechanisms in cancer drug resistance, thus providing new ideas for cancer treatment.
| S-EPMC7559774 | biostudies-literature