Dataset Information

TRNA-Derived Fragments in Podocytes with Adriamycin-Induced Injury Reveal the Potential Mechanism of Idiopathic Nephrotic Syndrome.

ABSTRACT: Idiopathic nephrotic syndrome (INS) is a disease involving injury to podocytes in the glomerular filtration barrier, and its specific causes have not been elucidated. Transfer RNA-derived fragments (tRFs), products of precise tRNA cleavage, have been indicated to play critical roles in various diseases. Currently, there is no relevant research on the role of tRFs in INS. This study intends to explore the changes in and importance of tRFs during podocyte injury in vitro and to further analyze the potential mechanism of INS. Differentially expressed tRFs in the adriamycin-treated group were identified by high-throughput sequencing and further verified by quantitative RT-PCR. In total, 203 tRFs with significant differential expression were identified, namely, 102 upregulated tRFs and 101 downregulated tRFs (q < 0.05, ?log2FC | ?2). In particular, AS-tDR-008924, AS-tDR-011690, tDR-003634, AS-tDR-013354, tDR-011031, AS-tDR-001008, and AS-tDR-007319 were predicted to be involved in podocyte injury by targeting the Gpr, Wnt, Rac1, and other genes. Furthermore, gene ontology analysis showed that these differential tRFs were strongly associated with podocyte injury processes such as protein binding, cell adhesion, synapses, the actin cytoskeleton, and insulin-activate receptor activity. KEGG pathway analysis predicted that they participated in the PI3K-Akt signaling pathway, Wnt signaling pathway, and Ras signaling pathway. It was reported that these pathways contribute to podocyte injury. In conclusion, our study revealed that changes in the expression levels of tRFs might be involved in INS. Seven of the differentially expressed tRFs might play important roles in the process of podocyte injury and are worthy of further study.

SUBMITTER: Li S

PROVIDER: S-EPMC7330628 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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tRNA-Derived Fragments in Podocytes with Adriamycin-Induced Injury Reveal the Potential Mechanism of Idiopathic Nephrotic Syndrome.

Li Shanwen S Liu Yiwen Y He Xiaowei X Luo Xiagang X Shi Huimin H Qu Gaoting G Wen Xianli X Gan Weihua W Wang Jun J Zhang Aiqing A

BioMed research international 20200622

Idiopathic nephrotic syndrome (INS) is a disease involving injury to podocytes in the glomerular filtration barrier, and its specific causes have not been elucidated. Transfer RNA-derived fragments (tRFs), products of precise tRNA cleavage, have been indicated to play critical roles in various diseases. Currently, there is no relevant research on the role of tRFs in INS. This study intends to explore the changes in and importance of tRFs during podocyte injury in vitro and to further analyze the ...[more]

PMID: 32685525

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Project description:BackgroundIschemia-reperfusion injury (IRI) is one of the major causes of acute kidney injury (AKI). tRNA derived fragments (tRFs/tiRNAs) are groups of small noncoding RNAs derived from tRNAs. To date, the role of tRFs/tiRNAs in renal IRI has not been reported. Herein, we aimed to investigate the involvement of tRFs/tiRNAs in the occurrence and development of ischemia-reperfusion-induced AKI.MethodsModerate/severe renal IRI mouse models were established by bilateral renal pedicle clamping. The tRF/tiRNA profiles of healthy controls and moderate/severe IRI-stressed kidney tissues were sequenced by Illumina NextSeq 500. Candidate differentially expressed tiRNAs were further verified by RT-qPCR. Biological analysis was also performed.ResultsOverall, 152 tRFs/tiRNAs were differentially expressed in the moderate ischemic injury group compared with the normal control group (FC > 2, p < 0.05), of which 47 were upregulated and 105 were downregulated; in the severe ischemic injury group, 285 tRFs/tiRNAs were differentially expressed (FC > 2, p < 0.05), of which 157 were upregulated, and 128 were downregulated. RT-qPCR determination of eight abundantly expressed tiRNAs was consistent with the sequencing results. Gene Ontology analysis for target genes of the tRFs/tiRNAs showed that the most enriched cell components, molecular functions and biological processes were Golgi apparatus, cytoplasmic vesicles, protein binding, cellular protein localization and multicellular organism development. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these target genes were mainly involved in the natural killer cell mediated cytotoxicity pathway, citrate cycle, and regulation of actin cytoskeleton signaling pathway.ConclusionOur results indicated that tRFs/tiRNAs were involved in renal IRI. These tRFs/tiRNAs may be effective partly via regulation of renal immunity, inflammation and metabolism processes. Candidate genes, including tiRNA-Gly-GCC-003, tiRNA-Lys-CTT-003, and tiRNA-His-GTG-002, might be potential biomarkers and therapeutic targets of ischemia-reperfusion injury-induced acute kidney injury.

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'.

Dataset Information

TRNA-Derived Fragments in Podocytes with Adriamycin-Induced Injury Reveal the Potential Mechanism of Idiopathic Nephrotic Syndrome.

Publications

tRNA-Derived Fragments in Podocytes with Adriamycin-Induced Injury Reveal the Potential Mechanism of Idiopathic Nephrotic Syndrome.

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