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Age-driven modulation of tRNA-derived fragments in Drosophila and their potential targets.

ABSTRACT: Development 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.Here 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.We 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.

SUBMITTER: Karaiskos S

PROVIDER: S-EPMC4572633 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Age-driven modulation of tRNA-derived fragments in Drosophila and their potential targets.

Karaiskos Spyros S Naqvi Ammar S AS Swanson Karl E KE Grigoriev Andrey A

Biology direct 20150916

<h4>Background</h4>Development 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.<h4>Results</h4>Here we describe Drosophila melanogaster tRFs, which appear to have a number of str ...[more]

PMID: 26374501

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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.

Project description:Pancreatic cancer is a deadly disease, the deadliest of all the solid tumors; the 5-year survival rate of patients with this disease is ~8%. Previously, high-throughput sequencing has led to the discovery of novel small non-coding RNAs, also known as transfer RNA-derived fragments (tRFs). Studies have suggested that tRFs may be novel biomarkers for certain diseases. However, the expression of tRFs in pancreatic cancer has yet to be characterized. In the present study, the expression levels of tRFs observed in clinical pancreatic cancer samples were analyzed, quantitative PCR (qPCR) was performed to validate the tRFs expression levels and bioinformatics predictions were analyzed. The results revealed that the pancreatic cancer samples screened out a total of 48 tRFs and transfer RNA halves (tiRNAs). There were four tRFs and tiRNAs selected for qPCR validation; the findings were consistent with the sequencing results. Bioinformatic predictions revealed that AS-tDR-000064 was predicted to have 2,450 target genes; AS-tDR-000069 was predicted 445 target genes; AS-tDR-000102 was predicted 746 target genes; and AS-tDR-001391 was predicted 216 target genes. Gene Ontology (GO) analyses demonstrated that the target genes of AS-tDR-000064 were mostly enriched in 'the regulation of cellular processes' (Biological Process), 'the synapses' (Cellular Component) and 'enzyme binding' (Molecular Function). The target genes of AS-tDR-000069 were mostly enriched in 'signaling' (Biological Process), 'the plasma membrane' (Cellular Component) and 'phosphatidylinositol 3-kinase (PI3K) binding'(Molecular Function), the target genes of AS-tDR-000102 were mostly enriched in 'axon development' (Biological Process), 'the synapse' (Cellular Component) and 'sequence-specific DNA binding' (Molecular Function) and the target genes of AS-tDR-001391 were mostly enriched in 'the neuromuscular processes' (Biological Process), the neurons' (Cellular Component) and 'PDZ domain binding' (Molecular Function). The Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that the target genes of AS-tDR-000064 were mostly enriched in 'the Ras signaling pathway', the target genes of AS-tDR-000069 were mostly enriched in 'the cancer pathways', the target genes of AS-tDR-000102 were mostly enriched in 'axon guidance' and the target genes of AS-tDR-001391 were mostly enriched in 'the PI3K/protein kinase-B signaling pathway'.

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Age-driven modulation of tRNA-derived fragments in Drosophila and their potential targets.

Publications

Age-driven modulation of tRNA-derived fragments in Drosophila and their potential targets.

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