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Emara, Mohamed M., Pavel Ivanov, Tyler Hickman, et al. "Angiogenin-induced tRNA-derived Stress-induced RNAs Promote Stress-induced Stress Granule Assembly." Journal of Biological Chemistry 285, no. 14 (2010): 10959–68. http://dx.doi.org/10.1074/jbc.m109.077560.
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Pereira, Marisa, Diana R. Ribeiro, Miguel M. Pinheiro, Margarida Ferreira, Stefanie Kellner, and Ana R. Soares. "m5U54 tRNA Hypomodification by Lack of TRMT2A Drives the Generation of tRNA-Derived Small RNAs." International Journal of Molecular Sciences 22, no. 6 (2021): 2941. http://dx.doi.org/10.3390/ijms22062941.
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Transfer RNA (tRNA) molecules contain various post-transcriptional modifications that are crucial for tRNA stability, translation efficiency, and fidelity. Besides their canonical roles in translation, tRNAs also originate tRNA-derived small RNAs (tsRNAs), a class of small non-coding RNAs with regulatory functions ranging from translation regulation to gene expression control and cellular stress response. Recent evidence indicates that tsRNAs are also modified, however, the impact of tRNA epitranscriptome deregulation on tsRNAs generation is only now beginning to be uncovered. The 5-methyluridine (m5U) modification at position 54 of cytosolic tRNAs is one of the most common and conserved tRNA modifications among species. The tRNA methyltransferase TRMT2A catalyzes this modification, but its biological role remains mostly unexplored. Here, we show that TRMT2A knockdown in human cells induces m5U54 tRNA hypomodification and tsRNA formation. More specifically, m5U54 hypomodification is followed by overexpression of the ribonuclease angiogenin (ANG) that cleaves tRNAs near the anticodon, resulting in accumulation of 5′tRNA-derived stress-induced RNAs (5′tiRNAs), namely 5′tiRNA-GlyGCC and 5′tiRNA-GluCTC, among others. Additionally, transcriptomic analysis confirms that down-regulation of TRMT2A and consequently m5U54 hypomodification impacts the cellular stress response and RNA stability, which is often correlated with tiRNA generation. Accordingly, exposure to oxidative stress conditions induces TRMT2A down-regulation and tiRNA formation in mammalian cells. These results establish a link between tRNA hypomethylation and ANG-dependent tsRNAs formation and unravel m5U54 as a tRNA cleavage protective mark.
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Wang, Mengjun, Junfeng Guo, Wei Chen, Hong Wang, and Xiaotong Hou. "Emerging roles of tRNA-derived small RNAs in injuries." PeerJ 12 (October 24, 2024): e18348. http://dx.doi.org/10.7717/peerj.18348.
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tRNA-derived small RNAs (tsRNAs) are a novel class of small noncoding RNAs, precisely cleaved from tRNA, functioning as regulatory molecules. The topic of tsRNAs in injuries has not been extensively discussed, and studies on tsRNAs are entering a new era. Here, we provide a fresh perspective on this topic. We systematically reviewed the classification, generation, and biological functions of tsRNAs in response to stress, as well as their potential as biomarkers and therapeutic targets in various injuries, including lung injury, liver injury, renal injury, cardiac injury, neuronal injury, vascular injury, skeletal muscle injury, and skin injury. We also provided a fresh perspective on the association between stress-induced tsRNAs and organ injury from a clinical perspective.
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Akiyama, Yasutoshi, Yoshika Takenaka, Tomoko Kasahara, Takaaki Abe, Yoshihisa Tomioka, and Pavel Ivanov. "RTCB Complex Regulates Stress-Induced tRNA Cleavage." International Journal of Molecular Sciences 23, no. 21 (2022): 13100. http://dx.doi.org/10.3390/ijms232113100.
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Under stress conditions, transfer RNAs (tRNAs) are cleaved by stress-responsive RNases such as angiogenin, generating tRNA-derived RNAs called tiRNAs. As tiRNAs contribute to cytoprotection through inhibition of translation and prevention of apoptosis, the regulation of tiRNA production is critical for cellular stress response. Here, we show that RTCB ligase complex (RTCB-LC), an RNA ligase complex involved in endoplasmic reticulum (ER) stress response and precursor tRNA splicing, negatively regulates stress-induced tiRNA production. Knockdown of RTCB significantly increased stress-induced tiRNA production, suggesting that RTCB-LC negatively regulates tiRNA production. Gel-purified tiRNAs were repaired to full-length tRNAs by RtcB in vitro, suggesting that RTCB-LC can generate full length tRNAs from tiRNAs. As RTCB-LC is inhibited under oxidative stress, we further investigated whether tiRNA production is promoted through the inhibition of RTCB-LC under oxidative stress. Although hydrogen peroxide (H2O2) itself did not induce tiRNA production, it rapidly boosted tiRNA production under the condition where stress-responsive RNases are activated. We propose a model of stress-induced tiRNA production consisting of two factors, a trigger and booster. This RTCB-LC-mediated boosting mechanism may contribute to the effective stress response in the cell.
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Sarais, Fabio, Alvaro Perdomo-Sabogal, Klaus Wimmers, and Siriluck Ponsuksili. "tiRNAs: Insights into Their Biogenesis, Functions, and Future Applications in Livestock Research." Non-Coding RNA 8, no. 3 (2022): 37. http://dx.doi.org/10.3390/ncrna8030037.
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Transfer RNA (tRNA)-derived small RNAs (tsRNAs) belong to a group of transfer ribonucleic acid (tRNA)-derived fragments that have recently gained interest as molecules with specific biological functions. Their involvement in the regulation of physiological processes and pathological phenotypes suggests molecular roles similar to those of miRNAs. tsRNA biogenesis under specific physiological conditions will offer new perspectives in understanding diseases, and may provide new sources for biological marker design to determine and monitor the health status of farm animals. In this review, we focus on the latest discoveries about tsRNAs and give special attention to molecules initially thought to be mainly associated with tRNA-derived stress-induced RNAs (tiRNAs). We present an outline of their biological functions, offer a collection of useful databases, and discuss future research perspectives and applications in livestock basic and applied research.
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Li, Chunmei, Jing Zhu, Han Jin, et al. "Regulation of plant gene expression by tsRNAs in response to abiotic stress." PeerJ 13 (May 23, 2025): e19487. https://doi.org/10.7717/peerj.19487.
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Objective Transfer RNA-derived small RNAs (tsRNAs) are emerging regulators of gene expression in response to abiotic stress. This review aims to summarize recent advances in the classification, biogenesis, and biological functions of tsRNAs, with a focus on their roles in plant stress responses and the methodologies for investigating these molecules. Methods We conducted a comprehensive literature search across PubMed, Web of Science, and Google Scholar using keywords such as “tRNA-derived small RNAs”, “abiotic stress”, “plant gene regulation”, and “RNA sequencing”. Studies were selected based on their relevance to tsRNA biogenesis pathways, stress-responsive mechanisms, and functional validation in plant systems. Classification of tsRNAs was performed according to cleavage site specificity and nucleotide length. Bioinformatic tools and experimental approaches for tsRNA identification, target prediction, and functional validation were evaluated. Results tsRNAs are categorized into two main types: tRNA-derived stress-induced RNAs (tiRNAs; 29–50 nt) and tRNA-derived fragments (tRFs; 14–40 nt). tiRNAs arise from anticodon loop cleavage by RNase A/T2, while tRFs are generated via Dicer-dependent or -independent pathways. These molecules regulate gene expression at transcriptional, post-transcriptional, and translational levels by interacting with AGO proteins, displacing translation initiation factors, and modulating stress granule assembly. In plants, tsRNAs respond dynamically to abiotic stresses (e.g., drought, salinity, heat), influencing stress signaling pathways and epigenetic modifications. Advanced sequencing techniques (e.g., cP-RNA-seq, RtcB sRNA-seq) and databases (PtRFdb, tRFanalyzer) have facilitated tsRNA discovery and functional annotation. Conclusions tsRNAs represent a versatile class of regulatory molecules in plant stress biology. Their ability to fine-tune gene expression underpins adaptive responses to environmental challenges. Future research should prioritize standardized methodologies for tsRNA profiling, elucidation of stress-specific biogenesis mechanisms, and exploration of their potential as biomarkers or therapeutic targets for crop improvement. Integrating tsRNA research with systems biology approaches will deepen our understanding of plant resilience mechanisms.
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Akiyama, Yasutoshi, Prakash Kharel, Takaaki Abe, Paul Anderson, and Pavel Ivanov. "Isolation and initial structure-functional characterization of endogenous tRNA-derived stress-induced RNAs." RNA Biology 17, no. 8 (2020): 1116–24. http://dx.doi.org/10.1080/15476286.2020.1732702.
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Yamasaki, Satoshi, Pavel Ivanov, Guo-fu Hu, and Paul Anderson. "Angiogenin cleaves tRNA and promotes stress-induced translational repression." Journal of Cell Biology 185, no. 1 (2009): 35–42. http://dx.doi.org/10.1083/jcb.200811106.
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Stress-induced phosphorylation of eIF2α inhibits global protein synthesis to conserve energy for repair of stress-induced damage. Stress-induced translational arrest is observed in cells expressing a nonphosphorylatable eIF2α mutant (S51A), which indicates the existence of an alternative pathway of translational control. In this paper, we show that arsenite, heat shock, or ultraviolet irradiation promotes transfer RNA (tRNA) cleavage and accumulation of tRNA-derived, stress-induced small RNAs (tiRNAs). We show that angiogenin, a secreted ribonuclease, is required for stress-induced production of tiRNAs. Knockdown of angiogenin, but not related ribonucleases, inhibits arsenite-induced tiRNA production and translational arrest. In contrast, knockdown of the angiogenin inhibitor RNH1 enhances tiRNA production and promotes arsenite-induced translational arrest. Moreover, recombinant angiogenin, but not RNase 4 or RNase A, induces tiRNA production and inhibits protein synthesis in the absence of exogenous stress. Finally, transfection of angiogenin-induced tiRNAs promotes phospho-eIF2α–independent translational arrest. Our results introduce angiogenin and tiRNAs as components of a phospho-eIF2α–independent stress response program.
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Li, Yan, Jun Luo, Hui Zhou, et al. "Stress-induced tRNA-derived RNAs: a novel class of small RNAs in the primitive eukaryote Giardia lamblia." Nucleic Acids Research 36, no. 19 (2008): 6048–55. http://dx.doi.org/10.1093/nar/gkn596.
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Зайченко, Д. М., А. Ю. Пасько, А. А. Микрюкова та ін. "Фрагменты транспортной РНК при клеточном старении, индуцированном стрессом эндоплазматического ретикулума". Zhurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» 68, № 1 (2024): 4–14. http://dx.doi.org/10.25557/0031-2991.2024.01.4-14.
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Транспортная РНК играет ключевую роль в жизнедеятельности клетки, обеспечивая процесс декодирования генетической информации в белковом синтезе. Как показывают последние исследования, молекула тРНК может выполнять другие функции благодаря процессингу. Расщепление пре-тРНК и зрелой тРНК приводит к образованию различных некодирующих РНК, среди которых так называемые половинки тРНК (tRNA halves), также известные как индуцированные стрессом РНК (stress-induced tRNA), tRNA-derived или tiRNA. Описаны также меньшие фрагменты тРНК (tRFs). Характерным примером «двойного назначения» тРНК является разрезание активируемой при клеточном стрессе нуклеазой ангиогенин тРНК в антикодоновой петле с генерацией половинок, из которых 5’-фрагменты опосредуют временное выключение трансляции при стрессе. Ранее нами было впервые показано увеличение содержания tiRNA при остром стрессе эндоплазматического ретикулума и способность хронического стресса ЭПР приводить к формированию фенотипа клеточного старения. В работе с помощью высокопроизводительного секвенирования впервые анализируется профиль фрагментов тРНК при ЭПР-стресс-индуцируемом старении и сопоставляется с профилем при репликативном старении. Обнаружен ряд общих фрагментов тРНК для этих двух состояний. Они потенциально могут использоваться в качестве маркеров процессов клеточного старения. Transfer RNA plays a key role in the cell, providing the process of decoding genetic information. Recent research shows that the tRNA molecule can perform other functions due to processing. Cleavage of pre-tRNA and mature tRNA leads to the formation of various non-coding RNAs, among which are so-called tRNA halves, also known as stress-induced tRNA, tRNA-derived or tiRNA. Smaller tRNA fragments (tRFs) have also been described. A typical example of «dual purpose» tRNA is the cutting of tRNA in the anticodon loop by cellular stress-activated nuclease angiogenin, generating halves, of which the 5’ fragments mediate temporary translation shutdown under stress. Previously, we demonstrated an increase in tiRNAs during acute endoplasmic reticulum stress and the ability of chronic ER stress to lead to the formation of a cellular senescence phenotype. In this work, using high-throughput sequencing, the profile of tRNA fragments during ER stress-induced cellular senescence is analyzed for the first time and compared with the profile during replicative senescence. A number of common tRNA fragments have been found for these two conditions. They can potentially be used as markers of cellular senescence.
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Yang, Changwon, Garam An, Jisoo Song, Gwonhwa Song, and Whasun Lim. "Palmitic acid induces inflammatory cytokines and regulates tRNA-derived stress-induced RNAs in human trophoblasts." Journal of Animal Reproduction and Biotechnology 37, no. 4 (2022): 218–25. http://dx.doi.org/10.12750/jarb.37.4.218.
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Wang, Xiaoming, Yining Yang, Xuyan Tan, et al. "Identification of tRNA-Derived Fragments Expression Profile in Breast Cancer Tissues." Current Genomics 20, no. 3 (2019): 199–213. http://dx.doi.org/10.2174/1389202920666190326145459.
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Background: In recent years, tRFs(transfer RNA-Derived Fragments) and transfer RNADerived Stress-induced RNAs (or tRNA halves) have been shown to have vital roles in cancer biology. We aimed to reveal the expression profile of tRNA-derived fragments in breast cancer tissues in the study, and to explore their potential as biomarkers of breast cancer. Methods: We characterized the tRNA-derived fragments expression profile from 6 paired clinical breast cancer tissues and adjacent normal samples. Then we selected 6 significantly expressed tRNAderived fragments and screened the genes for validation by using Quantitative Real-time PCR. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes biological pathway were finally analyzed. Results: We found 30 differentially expressed tRNA-derived fragments across our dataset, out of which 17 were up-regulated, and 13 were down-regulated. Compared with 16 clinical breast cancer tissues and adjacent normal tissues by qPCR, the results demonstrated that tRF-32-Q99P9P9NH57SJ (FC = -2.6476, p = 0.0189), tRF-17-79MP9PP (FC = -4.8984, p = 0.0276) and tRF-32- XSXMSL73VL4YK (FC = 6.5781, p = 0.0226) were significantly expressed in breast cancer tissues (p < 0.001). tRF-32-XSXMSL73VL4YK was significantly up-regulated, and tRF-32- Q99P9P9NH57SJ and tRF-17-79MP9PP were significantly down-regulated in which the expression patterns were similar to the sequencing results. The top ten significant results of GO and KEGG pathways enrichment analysis were presented. Conclusion: Our studies have demonstrated that there were significantly expressed tRNA-derived fragments in breast cancer tissues. They are hopefully to become biomarkers and would be valuable researches in this area.
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Saikia, Mridusmita, and Maria Hatzoglou. "The Many Virtues of tRNA-derived Stress-induced RNAs (tiRNAs): Discovering Novel Mechanisms of Stress Response and Effect on Human Health." Journal of Biological Chemistry 290, no. 50 (2015): 29761–68. http://dx.doi.org/10.1074/jbc.r115.694661.
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Deng, Lin, Housheng Wang, Ting Fan, et al. "Potential Functions of the tRNA-Derived Fragment tRF-Gly-GCC Associated With Oxidative Stress in Radiation-Induced Lung Injury." Dose-Response 20, no. 3 (2022): 155932582211287. http://dx.doi.org/10.1177/15593258221128744.
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Objective Transfer RNA-derived small RNAs (tsRNAs) are a novel type of non-coding RNA with various regulatory functions. They are associated with oxidative stress in various diseases, but their potential functions in radiation-induced lung injury (RILI) remain uncertain. Methods To explore the role of tsRNAs in RILI, we used X-rays to irradiate human bronchial epithelial cells and examined the expression profile of altered tsRNAs by RNA sequencing and bioinformatics analysis. Sequencing results were verified by qRT-PCR. tsRNA functions were explored using several methods, including CCK-8, reactive oxygen species (ROS) assays, cell transfection, and western blotting. Results Eighty-six differentially expressed tRNA-derived fragments (tRFs) were identified: 64 were upregulated, and 22 were downregulated. Among them, the regulation of tRF-Gly-GCC, associated with oxidative stress, may be mediated by the inhibition of cell proliferation, promotion of ROS production, and apoptosis in the occurrence and development of RILI. A Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that the underlying molecular mechanism may involve the PI3K/AKT and the FOXO1 signaling pathways. Conclusion Our findings provide new insights into the molecular mechanisms underpinning RILI, advancing the clinical prevention and treatment of this disease.
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Ma, Zhuoyao, Ningyuan Tang, Ruiyan Zhang, et al. "Ribonuclease Inhibitor 1 (RNH1) Regulates Sperm tsRNA Generation for Paternal Inheritance through Interacting with Angiogenin in the Caput Epididymis." Antioxidants 13, no. 8 (2024): 1020. http://dx.doi.org/10.3390/antiox13081020.
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Environmental stressors can induce paternal epigenetic modifications that are a key determinant of the intergenerational inheritance of acquired phenotypes in mammals. Some of them can affect phenotypic expression through inducing changes in tRNA-derived small RNAs (tsRNAs), which modify paternal epigenetic regulation in sperm. However, it is unclear how these stressors can affect changes in the expression levels of tsRNAs and their related endonucleases in the male reproductive organs. We found that Ribonuclease inhibitor 1 (RNH1), an oxidation responder, interacts with ANG to regulate sperm tsRNA generation in the mouse caput epididymis. On the other hand, inflammation and oxidative stress induced by either lipopolysaccharide (LPS) or palmitate (PA) treatments weakened the RNH1-ANG interaction in the epididymal epithelial cells (EEC). Accordingly, ANG translocation increased from the nucleus to the cytoplasm, which led to ANG upregulation and increases in cytoplasmic tsRNA expression levels. In conclusion, as an antioxidant, RNH1 regulates tsRNA generation through targeting ANG in the mouse caput epididymis. Moreover, the tsRNA is an epigenetic factor in sperm that modulates paternal inheritance in offspring via the fertilization process.
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Kfoury, Youmna, Fei Ji, Michael Mazzola, et al. "Niche Transfer of Small Non-Coding RNAs Regulates Hematopoietic Response to Stress." Blood 134, Supplement_1 (2019): 1207. http://dx.doi.org/10.1182/blood-2019-124794.
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The bone marrow (BM) niche, is an extrinsic regulator of hematopoietic stem and progenitor cells (HSPCs) (Morrison and Scadden 2014). The niche can drive disease and loss of HSPC function (Raaijmakers et al., 2010; Kode et al., 2014; Dong et al., 2016). Of particular interest, deletion in specific niche cells of the small RNA processing enzymes, Dicer1 and Angiogenin (Ang1) resulted in hematopoietic transformation (Raaijmakers et al., 2010) and loss of HSC quiescence (Goncalves et al., 2016), respectively. We tested mechanisms by which small non-coding RNAs (sncRNA) from niche cells might contribute to HSPC regulation. The transfer of cytoplasmic contents from specific mesenchymal subsets to wild type (WT) transplanted hematopoietic cells was evaluated by GFP. Osteoblastic cell reporter mice (Ocn-GFP, Col1-GFP) transferred 40-fold more GFP to HSPC than mesenchymal stem cells (Nes-GFP) or osteoprogenitors (Osx-GFP). GFP cannot transfer through gap junctions, however 100nM extracellular vesicles (EVs) labeled with the endocytic marker TSG-101 and GFP were found in Ocn-GFP bone marrow plasma. Granulocyte macrophage progenitor (GMPs) cells were the major hematopoietic recipients of osteoblast derived EVs (Fig. 1A). Small RNA analysis of mouse BM EVs demonstrated >85% were tRNA (Fig. 1B) while Northern blot (NB) revealed both tRNAs and stress induced RNAs (tiRNAs) (Fig. 1C). tRNAs were evident in EVs and in EV generating and recipient cells, while tiRNAs were highly enriched in EVs compared to cells (Fig. 1C). Extracellular vesicle recipient and non-recipient GMPs (GMP[GFP+] and GMP[GFP-]) respectively demonstrated a 2-fold enrichment in reads mapping to tRNAs in GMP[GFP+]. Principle component analysis demonstrated that the two populations are distinct in their tRNA content. In addition, twelve specific tRNAs were present at a significantly higher levels in GMP[GFP+]. Gene expression analysis of GMP[GFP+]and GMP[GFP-] revealed an enrichment of protein translation and cell cycle related functions in GMP[GFP+] which were validated using an in vivo protein translation assay and cell cycle analyses. Synthetic oligos corresponding to the sequence of top ten tiRNAs that are enriched in GMP[GFP+] were transfected into primary GMPs. 5'-Pro-CGG-1 and 5'-Cys-GCA-27 increased the rate of protein translation and cellular proliferation in transfected GMPs (Fig. 1D-E). The physiologic relevance of EV transfer was assessed using two stress states, systemic Candida albicans infection and low dose gamma irradiation. The frequency of GMP[GFP+] increased in both states in concert with increased cell proliferation. Therefore, EV transfer of sncRNAs from niche to hematopoietic progenitors in vivo is a rapid means of conveying information between cells. It alters progenitor protein translation and proliferation in a manner responsive to stress. The transfer of 5'tiRNA EV from specific niche cells to specific hematopoietic cells is an additional mechanism for niche regulation of blood cell production. Disclosures Sykes: Clear Creek Bio: Equity Ownership, Other: Co-Founder. Scadden:Clear Creek Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Fog Pharma: Consultancy; Agios Pharmaceuticals: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; LifeVaultBio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Editas Medicine: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bone Therapeutics: Consultancy; Novartis: Other: Sponsored research; Fate Therapeutics: Consultancy, Equity Ownership; Red Oak Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
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Chen, Hui, Zhiying Xu, Hua Cai, Ya Peng, Li Yang, and Zhen Wang. "Identifying Differentially Expressed tRNA-Derived Small Fragments as a Biomarker for the Progression and Metastasis of Colorectal Cancer." Disease Markers 2022 (January 6, 2022): 1–10. http://dx.doi.org/10.1155/2022/2646173.
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Objectives. The epithelial-to-mesenchymal transition (EMT) is one key step for the invasion and metastasis of colorectal cancer (CRC). Up until now, the underlying mechanism of EMT in CRC is still unpromising. Thus, it is essential to have a better understanding of its carcinogenesis. The transfer RNA-derived small fragments (tsRNAs) are a new group of small noncoding RNAs (sncRNAs), including tRNA-derived stress-induced RNAs (tiRNAs) and tRNA-derived fragments (tRFs), which have been observed to play an important role in many cancers. However, the relationship between tRFs and EMT in CRC is still unknown. Herein, we aimed to investigate the involvement of tRFs in EMT and its contribution to CRC development. Methods. We identified the differentially expressed tsRNAs in colorectal cancer cell line HT29 treated with TGF-β compared with control cells by using high-throughput sequencing and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). QRT-PCR was conducted to validate the differentially expressed fragments in 68 CRC tumor samples (22 women and 46 men) and adjacent nontumor samples. The association of the expression of tRFs with CRC metastasis and clinical stage was analyzed. Meanwhile, the correlation between tRF expression and overall survival (OS) was also analyzed. TargetScan and miRanda and multiple bioinformatic approaches were used to predict the possible target genes of tsRNAs and analyze possible functions of the tRFs. Results. A series of differentially expressed tsRNAs were identified in TGF-β-treated HT29 cells compared with control cells. tRF-phe-GAA-031 and tRF-VAL-TCA-002 were found to be significantly upregulated in CRC tissues compared to adjacent nontumor tissues. They were significantly correlated with distant metastasis and clinical stage. We compared the differences between tumor samples and nontumor tissues from the ROC curves. The area under the ROC curve (AUC) was up to 0.7554 (95% confidence interval: 0.6739 to 0.8369, p < 0.0001 ) for tRF-Phe-GAA-031 and up to 0.7313 (95% confidence interval: 0.6474 to 0.8151, p < 0.0001 ) for tRF-VAL-TCA-002. For OS analysis, higher tRF-phe-GAA-031 and tRF-VAL-TCA-002 expressions were associated with shorter survival for CRC patients. Conclusion. A series of differentially expressed tsRNAs are identified in the EMT process of CRC. And tRF-phe-GAA-031 and tRF-VAL-TCA-002 are higher expressed in CRC tissues, and they might play an important role in the metastasis of CRC. Meanwhile, they may be potential biomarkers and intervention targets in the clinical treatment of CRC.
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Sapetschnig, Alexandra, Beth Thomas, Eliza Yankova, et al. "Abstract LB171: First-in-class inhibitors of the tRNA methyltransferase METTL1 for the treatment of cancer." Cancer Research 84, no. 7_Supplement (2024): LB171. http://dx.doi.org/10.1158/1538-7445.am2024-lb171.
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Abstract METTL1 is an RNA methyltransferase that catalyzes N7-methylation on guanine at position 46 (m7G46) in a subset of transfer RNAs (tRNAs). These tRNAs are stabilized by m7G46, and this increases the translation of mRNAs containing the cognate codons. METTL1 is often over-expressed in cancer tissue, and its gene locus is frequently amplified in specific tumor types. Recent studies have shown that reducing METTL1 expression leads to tumor growth inhibition highlighting this enzyme as a potential novel target for anti-cancer drugs. We optimized small molecule inhibitors of METTL1 from a HTS hit using structure-guided medicinal chemistry. Representative compounds of two distinct chemical series exhibit potent in vitro METTL1 inhibition at low nanomolar concentrations while displaying exquisite selectivity over other RNA and protein methyltransferases. The effects of inhibiting METTL1 were measured by cellular mechanistic assays and modification-induced misincorporation tRNA sequencing (mim-tRNAseq). As expected, pharmacological inhibition led to decreased m7G46 methylation, lower levels of a subgroup of tRNAs and reduced cancer cell proliferation.The efficacy of METTL1 inhibition in a panel of cancer cell lines representing a wide range of solid and hematologic tumor types was determined. Cell proliferation was impaired in a subset of cell lines originating from various cancer types, including lymphoma, sarcoma, esophageal squamous cell carcinoma, glioblastoma, colorectal and lung adenocarcinoma. Importantly, viability was not affected in non-transformed cell lines, indicating a highly selective mechanism of action. The phenotypic consequences of METTL1 inhibition in selected cell lines were further investigated by flow cytometry and western blotting. Cell lines sensitive to METTL1 inhibition displayed reduced cell cycle progression and lowered expression of cell cycle regulators. RNA sequencing and proteome analyses identified molecular changes at both transcript and protein level. METTL1 inhibition led to induction of ATF4 expression and activation of the integrated stress response, as well as global changes to the translation machinery. Studies on cell-line derived xenograft or syngeneic in vivo mouse models were conducted to assess tumor growth inhibition after oral or intraperitoneal administration of the potent METTL1 small molecule inhibitor STM9005. Inhibition of METTL1 by this compound reduced tumor growth in both immune-deficient and immune-competent mouse models, effects accompanied by dose-dependent changes in pharmacodynamic biomarkers. Here, we describe the discovery of first-in-class inhibitors of METTL1 tRNA methyltransferase. To our knowledge, our data provide the first evidence that pharmacological inhibition of a tRNA methyltransferase reduces tumor growth in vivo. Citation Format: Alexandra Sapetschnig, Beth Thomas, Eliza Yankova, Harry Fischl, Aleksandra Azevedo, Sarah Bucknell, Richard Fosbeary, Sapphire Sawyer, Sian Evans, Carmen Livi, Byron Andrews, Jack Rogan, Natalie Webster, Matthew Fyfe, Konstantinos Tzelepis, Oliver Rausch. First-in-class inhibitors of the tRNA methyltransferase METTL1 for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB171.
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Takenaka, Yoshika, Asuka Yamada, Yoshihisa Tomioka, Yasutoshi Akiyama, and Pavel Ivanov. "RNase L Produces tRNA-derived RNAs that Contribute to Translation Inhibition." RNA, April 15, 2025, rna.080419.125. https://doi.org/10.1261/rna.080419.125.
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Ribonuclease L (RNase L) is an RNase which is activated by viral double-stranded RNAs (dsRNAs). RNase L cleaves not only viral RNAs but also host RNAs including mRNAs and tRNAs, which contributes to innate immune defense against viruses. While it has been reported that RNase L-mediated bulk mRNA cleavage induces rapid translation repression independently of the integrated stress response, the significance of RNase L-mediated tRNA cleavage remains largely unknown. Here we show that RNase L cleaves various tRNA species in the anticodon loops, generating transfer RNA-derived RNAs (tDRs) similar to tRNA-derived stress-induced RNAs (tiRNAs) that are generated by a stress-responsive RNase angiogenin (ANG). Three tRNA species (tRNALeu, tRNASeC and tRNASer) were cleaved within the variable loops as well as in the anticodon loops by RNase L, generating non-canonical tDRs. As RNase L-induced 5'-tDRAla/Cys were similar in length to 5'-tiRNAAla/Cys that possess a translation inhibitory effect, we examined whether RNase L-induced 5'-tDRAla also inhibited translation. In vitro translation analysis showed that RNase L-induced 5'-tDRAla significantly inhibits mRNA translation like 5'-tiRNAAla, suggesting that the production of 5'-tDRAla may be involved in the mechanism of RNase L-mediated stress response during viral infection. Our data shed new light on the potential roles of tDRs in innate immunity against viral infection.
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Mao, Mingwen, Weina Chen, Xingbiao Huang, and Dong Ye. "Role of tRNA-derived small RNAs(tsRNAs) in the diagnosis and treatment of malignant tumours." Cell Communication and Signaling 21, no. 1 (2023). http://dx.doi.org/10.1186/s12964-023-01199-w.
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AbstractMalignant tumours area leading cause of death globally, accounting for approximately 13% of all deaths. A detailed understanding of the mechanism(s) of the occurrence and development of malignant tumours and identification of relevant therapeutic targets are therefore key to tumour treatment. tsRNAs(tRNA-derived small RNAs)—also known as TRFs (tRNA-derived fragments), tiRNAs (tRNA-derived stress-induced RNAs), tRNA halves, etc.—are a recently identified class of small noncoding RNAs that are generated from mature tRNA or tRNA precursors through cleavage by enzymes such as angiogenin, Dicer, RNase Z, and RNase P. Several studies have confirmed that dysregulation of tsRNAs is closely related to the tumorigenesis of breast cancer, nasopharyngeal cancer, lung cancer, and so on. Furthermore, research indicates that tsRNAs can be used as clinical diagnostic markers and therapeutic targets for cancer. In our review, we summarized the recent research progress on the role and clinical application of tsRNAs in tumorigenesis and progression.
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Pereira, Marisa, Ribeiro Diana R., Pinheiro Miguel M., Margarida Ferreira, Stefanie Kellner, and Ana R. Soares. "m5U54 tRNAHypomodification by Lack of TRMT2ADrivesthe Generation of tRNA-Derived Small RNAs." International Journal of Molecular Sciences 22, no. 6 (2021). https://doi.org/10.3390/ijms22062941.
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Hogg, Marion. "tRNA fragment biomarkers of Neurological Disease: Challenges and Opportunities." Medical Research Archives 11, no. 3 (2023). http://dx.doi.org/10.18103/mra.v11i3.3688.
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Transfer RNAs play a crucial role in protein translation where they bring amino acids to the ribosome to be incorporated into nascent polypeptide chains. During stress conditions tRNAs can be cleaved to generate tRNA-derived fragments. Several ribonucleases have been identified that cleave tRNA, however mutations in the stress-induced ribonuclease Angiogenin have been identified in a range of neurological disorders including Amyotrophic Lateral Sclerosis, Parkinson’s Disease, and Alzheimer’s Disease, suggesting that tRNA cleavage may be dysregulated in neurological disease. tRNA fragments have been detected in biofluids indicating they may be of use as biomarkers for neurological diseases. There is considerable variability in the methods used to quantify tRFs from size selection, adapter ligation, removal of RNA modifications, and sequence analysis approaches which can make it difficult to reconcile multiple studies. Here we review the biology of transfer RNAs and the biogenesis of tRNA-derived fragments, with a focus on the methods used to identify and quantify tRNA fragments and how different methodological approaches can influence tRNA fragment detection. We provide an overview of current literature on the identification of tRNA fragments in neurological disease models and patient samples, with a focus on circulating tRNA fragments as potential biomarkers of neurological diseases.
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Wang, Chaojun, Weiqiang Chen, Maimaiti Aili, Lei Zhu, and Yan Chen. "tRNA-derived small RNAs in plant response to biotic and abiotic stresses." Frontiers in Plant Science 14 (January 30, 2023). http://dx.doi.org/10.3389/fpls.2023.1131977.
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tRNA-derived small RNAs (tsRNAs) represent a novel category of small non-coding RNAs and serve as a new regulator of gene expression at both transcriptional and post-transcriptional levels. Growing evidence indicates that tsRNAs can be induced by diverse stimuli and regulate stress-responsive target genes, allowing plants to adapt to unfavorable environments. Here, we discuss the latest developments about the biogenesis and classification of tsRNAs and highlight the expression regulation and potential function of tsRNAs in plant biotic and abiotic stress responses. Of note, we also collect useful bioinformatics tools and resources for tsRNAs study in plants. Finally, we propose current limitations and future directions for plant tsRNAs research. These recent discoveries have refined our understanding of whether and how tsRNAs enhance plant stress tolerance.
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Zhang, Liou, Jie Liu, and Yang Hou. "Classification, function, and advances in tsRNA in non-neoplastic diseases." Cell Death & Disease 14, no. 11 (2023). http://dx.doi.org/10.1038/s41419-023-06250-9.
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AbstracttRNA-derived small RNAs (tsRNAs) are non-coding small RNAs produced by specific endonucleases following the processing and splicing of precursor or mature tRNAs upon starvation, oxidative stress, hypoxia, and other adverse conditions. tRNAs are classified into two major categories, tRNA fragments (tRFs) and tRNA-derived stress-induced small RNAs (tiRNAs), based on differences in splice sites. With the development of high-throughput sequencing technologies in recent years, tsRNAs have been found to have important biological functions, including inhibition of apoptosis, epigenetic regulation, cell–cell communication, translation, and regulation of gene expression. Additionally, these molecules have been found to be aberrantly expressed in various diseases and to be involved in several pathological processes. In this article, the classification and nomenclature, biological functions, and potential use of tsRNAs as diagnostic biomarkers and therapeutic targets in non-neoplastic diseases are reviewed. Although tsRNA research is at its infancy, their potential in the treatment of non-tumor diseases warrants further investigation.
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Lou, Yuming, Bifei Fu, Lutong Liu, Jialu Song, Mengying Zhu, and Chaoyang Xu. "The tRF-33/IGF1 Axis Dysregulates Mitochondrial Homeostasis in HER2-Negative Breast Cancer." American Journal of Physiology-Cell Physiology, January 10, 2025. https://doi.org/10.1152/ajpcell.00588.2024.
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Transfer RNA-derived small RNAs (tsRNAs), a recently identified non-coding RNA subset, are mainly classified into tRNA-derived small RNA fragments (tRFs) and tRNA-derived stress-induced RNAs (tiRNAs). tsRNAs dysregulation is frequently observed in numerous cancer types, suggesting involvement in tumorigenesis. However, their functions in breast cancer (BC) remain to be fully understood. Here, it was discovered that tRF-33-MEF91SS2PMFI0Q (tRF-33), derived from mature tRNA-LysTTT, was markedly upregulated in HER2-negative BC cells and tissue samples. tRF-33 stimulated the proliferation, migration, and invasiveness of BC cells in vitro and facilitated tumor progression in vivo. Mechanistically, tRF-33 was found for the first time to bind directly to the 3’-UTR of IGF1, resulting in downregulation of both its mRNA and protein and thus affecting mitochondrial homeostasis and progression of BC. These results demonstrate a novel tsRNA modulatory mechanism and a potential direction for treating HER2-negative BC.
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Drino, Aleksej, Lisa König, Charlotte Capitanchik, et al. "Identification of RNA helicases with unwinding activity on angiogenin-processed tRNAs." Nucleic Acids Research, January 31, 2023. http://dx.doi.org/10.1093/nar/gkad033.
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Abstract Stress-induced tRNA fragmentation upon environmental insult is a conserved cellular process catalysed by endonucleolytic activities targeting mature tRNAs. The resulting tRNA-derived small RNAs (tsRNAs) have been implicated in various biological processes that impact cell-to-cell signalling, cell survival as well as gene expression regulation during embryonic development. However, how endonuclease-targeted tRNAs give rise to individual and potentially biologically active tsRNAs remains poorly understood. Here, we report on the in vivo identification of proteins associated with stress-induced tsRNAs-containing protein complexes, which, together with a ‘tracer tRNA’ assay, were used to uncover enzymatic activities that can bind and process specific endonuclease-targeted tRNAs in vitro. Among those, we identified conserved ATP-dependent RNA helicases which can robustly separate tRNAs with endonuclease-mediated ‘nicks’ in their anticodon loops. These findings shed light on the existence of cellular pathways dedicated to producing individual tsRNAs after stress-induced tRNA hydrolysis, which adds to our understanding as to how tRNA fragmentation and the resulting tsRNAs might exert physiological impact.
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Sanadgol, Nasim, Lisa König, Alexej Drino, Michaela Jovic, and Matthias R. Schaefer. "Experimental paradigms revisited: oxidative stress-induced tRNA fragmentation does not correlate with stress granule formation but is associated with delayed cell death." Nucleic Acids Research, June 14, 2022. http://dx.doi.org/10.1093/nar/gkac495.
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Abstract tRNA fragmentation is an evolutionarily conserved molecular phenomenon. tRNA-derived small RNAs (tsRNAs) have been associated with many cellular processes, including improved survival during stress conditions. Here, we have revisited accepted experimental paradigms for modeling oxidative stress resulting in tRNA fragmentation. Various cell culture models were exposed to oxidative stressors followed by determining cell viability, the production of specific tsRNAs and stress granule formation. These experiments revealed that exposure to stress parameters commonly used to induce tRNA fragmentation negatively affected cell viability after stress removal. Quantification of specific tsRNA species in cells responding to experimental stress and in cells that were transfected with synthetic tsRNAs indicated that neither physiological nor non-physiological copy numbers of tsRNAs induced the formation of stress granules. Furthermore, the increased presence of tsRNA species in culture medium collected from stressed cells indicated that cells suffering from experimental stress exposure gave rise to stable extracellular tsRNAs. These findings suggest a need to modify current experimental stress paradigms in order to allow separating the function of tRNA fragmentation during the acute stress response from tRNA fragmentation as a consequence of ongoing cell death, which will have major implications for the current perception of the biological function of stress-induced tsRNAs.
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Fallet, Manon, Rachel Wilson, and Peter Sarkies. "Cisplatin exposure alters tRNA-derived small RNAs but does not affect epimutations in C. elegans." BMC Biology 21, no. 1 (2023). http://dx.doi.org/10.1186/s12915-023-01767-z.
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Abstract Background The individual lifestyle and environment of an organism can influence its phenotype and potentially the phenotype of its offspring. The different genetic and non-genetic components of the inheritance system and their mutual interactions are key mechanisms to generate inherited phenotypic changes. Epigenetic changes can be transmitted between generations independently from changes in DNA sequence. In Caenorhabditis elegans, epigenetic differences, i.e. epimutations, mediated by small non-coding RNAs, particularly 22G-RNAs, as well as chromatin have been identified, and their average persistence is three to five generations. In addition, previous research showed that some epimutations had a longer duration and concerned genes that were enriched for multiple components of xenobiotic response pathways. These results raise the possibility that environmental stresses might change the rate at which epimutations occur, with potential significance for adaptation. Results In this work, we explore this question by propagating C. elegans lines either in control conditions or in moderate or high doses of cisplatin, which introduces genotoxic stress by damaging DNA. Our results show that cisplatin has a limited effect on global small non-coding RNA epimutations and epimutations in gene expression levels. However, cisplatin exposure leads to increased fluctuations in the levels of small non-coding RNAs derived from tRNA cleavage. We show that changes in tRNA-derived small RNAs may be associated with gene expression changes. Conclusions Our work shows that epimutations are not substantially altered by cisplatin exposure but identifies transient changes in tRNA-derived small RNAs as a potential source of variation induced by genotoxic stress.
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Baindoor, Sharada, Hesham A. Y. Gibriel, Morten T. Venø, et al. "Distinct fingerprints of tRNA-derived small non-coding RNA in animal models of neurodegeneration." Disease Models & Mechanisms 17, no. 11 (2024). http://dx.doi.org/10.1242/dmm.050870.
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ABSTRACT Transfer RNA-derived small RNAs (tsRNAs) – categorized as tRNA-derived fragments (tRFs), tRNA-derived stress-induced RNAs (tiRNAs) and internal tRF (itRF) – are small non-coding RNAs that participate in various cellular processes such as translation inhibition and responses to cellular stress. We here identified tsRNA profiles within susceptible tissues in animal models of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Parkinson's disease (PD) to pinpoint disease-specific tsRNAs and those shared across neurodegenerative diseases. We performed small RNA sequencing in the SOD1G93A and TDP43A315T mouse models of ALS (spinal cord), the TauP301S model of FTD (hippocampus), and the parkin/POLG model of PD (substantia nigra). Bioinformatic analysis showed higher expression of 5′ tiRNAs selectively in the two ALS models, lower expression of 3′ tRFs in both the ALS and FTD mouse models, and lower expression of itRF Arg in the PD model. Experimental validation confirmed the expression of tsRNAs. Gene Ontology analysis of targets associated with validated 3′ tRFs indicated functions in the regulation of synaptic and neuronal pathways. Our profiling of tsRNAs indicates disease-specific fingerprints in animal models of neurodegeneration, which require validation in human disease.
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Hogg, Marion C., Megan Rayner, Sergej Susdalzew, et al. "5′ValCAC tRNA fragment generated as part of a protective angiogenin response provides prognostic value in amyotrophic lateral sclerosis." Brain Communications 2, no. 2 (2020). http://dx.doi.org/10.1093/braincomms/fcaa138.
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Abstract Loss-of-function mutations in the ribonuclease angiogenin are associated with amyotrophic lateral sclerosis. Angiogenin has been shown to cleave transfer RNAs during stress to produce ‘transfer-derived stress-induced RNAs’. Stress-induced tRNA cleavage is preserved from single-celled organisms to humans indicating it represents part of a highly conserved stress response. However, to date, the role of tRNA cleavage in amyotrophic lateral sclerosis remains to be fully elucidated. To this end, we performed small RNA sequencing on a human astrocytoma cell line to identify the complete repertoire of tRNA fragments generated by angiogenin. We found that only a specific subset of tRNAs is cleaved by angiogenin and identified 5′ValCAC transfer-derived stress-induced RNA to be secreted from neural cells. 5′ValCAC was quantified in spinal cord and serum from SOD1G93A amyotrophic lateral sclerosis mouse models where we found it to be significantly elevated at symptom onset correlating with increased angiogenin expression, imbalanced protein translation initiation factors and slower disease progression. In amyotrophic lateral sclerosis patient serum samples, we found 5′ValCAC to be significantly higher in patients with slow disease progression, and interestingly, we find 5′ValCAC to hold prognostic value for amyotrophic lateral sclerosis patients. Here, we report that angiogenin cleaves a specific subset of tRNAs and provide evidence for 5′ValCAC as a prognostic biomarker in amyotrophic lateral sclerosis. We propose that increased serum 5′ValCAC levels indicate an enhanced angiogenin-mediated stress response within motor neurons that correlates with increased survival. These data suggest that the previously reported beneficial effects of angiogenin in SOD1G93A mice may result from elevated levels of 5′ValCAC transfer RNA fragment.
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Fang, Yuan, Yang Liu, Yu Yan, et al. "Differential Expression Profiles and Function Predictions for tRFs & tiRNAs in Skin Injury Induced by Ultraviolet Irradiation." Frontiers in Cell and Developmental Biology 9 (August 10, 2021). http://dx.doi.org/10.3389/fcell.2021.707572.
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Ultraviolet (UV) radiation is a major environmental factor contributing skin damage. As UV exposure is inevitable, it is necessary to pay attention to the underlying molecular mechanisms of UV-induced skin damage to develop effective therapies. tRNA-derived stress-induced RNAs (tiRNAs) and tRNA-derived fragments (tRFs) are tRNA-derived small RNAs (tsRNAs) that are a novel class of short, non-coding RNAs. However, the functions behind tRFs &amp; tiRNAs in UV-induced skin injury are not yet clear. Firstly, the animal model of ultraviolet irradiation induced skin damage was established. Then the skin samples were preserved for the follow-up experiment. Sequencing was used to screen expression profiles and predict target genes. Compared with normal skin, a total of 31 differentially expressed tRFs &amp; tiRNAs were screened. Among these, 10 tRFs &amp; tiRNAs were shown to be significantly different in expression levels, where there were 4 up-regulated and 6 down-regulated target genes. Bioinformatics analyses revealed potential up-regulated tsRNAs (tRF-Val-AAC-012, tRF-Pro-AGG-012, tRF-Val-CAC-018, tRF-Val-AAC-031) and down-regulated tsRNAs (tRF-Arg-CCT-002, tRF-Trp-TCA-001, tiRNA-Ser-GCT-001, tRF-Gly-CCC-019, tRF-Ala-TGC-001, tRF-Ala-TGC-002). In summary, it was speculated that tRF-Gly-CCC-019 plays an important role in acute skin injury induced by UVB radiation by regulating the ras-related C3 botulinum toxin substrate 1 (Rac1) gene in the WNT signaling pathway. This study provides new insights into the mechanisms and therapeutic targets of UV-induced skin injury.
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Akiyama, Yasutoshi, Shawn M. Lyons, Marta M. Fay, et al. "Selective Cleavage at CCA Ends and Anticodon Loops of tRNAs by Stress-Induced RNases." Frontiers in Molecular Biosciences 9 (March 1, 2022). http://dx.doi.org/10.3389/fmolb.2022.791094.
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Stress-induced tRNA cleavage has been implicated in various cellular processes, where tRNA fragments play diverse regulatory roles. Angiogenin (ANG), a member of the RNase A superfamily, induces cleavage of tRNAs resulting in the formation of tRNA-derived stress-induced RNAs (tiRNAs) that contribute to translational reprogramming aiming at cell survival. In addition to cleaving tRNA anticodon loops, ANG has been shown to cleave 3′-CCA termini of tRNAs in vitro, although it is not known whether this process occurs in cells. It has also been suggested that tiRNAs can be generated independently of ANG, although the role of other stress-induced RNases in tRNA cleavage is poorly understood. Using gene editing and biochemical approaches, we examined the involvement of ANG in stress-induced tRNA cleavage by focusing on its cleavage of CCA-termini as well as anticodon loops. We show that ANG is not responsible for CCA-deactivation under sodium arsenite (SA) treatment in cellulo, and although ANG treatment significantly increases 3′-tiRNA levels in cells, the majority of 3′-tiRNAs retain their 3′-CCA termini. Instead, other RNases can cleave CCA-termini in cells, although with low efficiency. Moreover, in the absence of ANG, other RNases are able to promote the production of tiRNAs in cells. Depletion of RNH1 (an endogenous inhibitor of RNase A superfamily) promotes constitutively-produced tiRNAs and CCA-deactivated tRNAs in cells. Interestingly, SA treatment in RNH1-depleted cells did not increase the amount of tiRNAs or CCA-deactivated tRNAs, suggesting that RNase A superfamily enzymes are largely responsible for SA-induced tRNA cleavage. We show that interplay between stress-induced RNases cause targeting tRNAs in a stress-specific manner in cellulo.
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Ng, N., H. A. Y. Gibriel, L. Halang, et al. "tRNA derived fragments are altered in diabetes." Diabetic Medicine, November 7, 2023. http://dx.doi.org/10.1111/dme.15258.
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AbstractAimsMaternally inherited Diabetes and Deafness (MIDD) is a rare form of adult‐onset diabetes that can be difficult to diagnose due to its variable clinical phenotype. Transfer RNA‐derived small fragments are a novel, emerging class of small noncoding RNAs (sncRNAs) that have significant potential as serum biomarkers due to their stress‐induced generation, abundance, stability, and ease of detection.MethodsWe investigated the levels of tiRNA 5’ValCAC (alone and in combination with miR‐23b‐3p) identified from small‐RNA sequencing studies in serum samples from healthy controls, Type 1 Diabetes, Type 2 Diabetes, and MIDD subjects.ResultsSerum levels of 5’ValCAC were reduced in MIDD and Type 2 diabetes subjects compared to controls. Type 2 diabetes subjects had higher serum levels of miR‐23b‐3p compared to all other subjects. Receiver Operating Characteristic analysis showed the potential of 5’ValCAC and miR‐23b‐3p as MIDD biomarkers, with the combination showing excellent separation from type 2 diabetes subjects.ConclusionsThis is the first report showing altered serum levels of tiRNAs in diabetes subjects. The combined use of 5’ValCAC and miR‐23b‐3p as serum biomarkers could potentially differentiate between MIDD subjects and Type 2 diabetes subjects.
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Li, Guoping, Manning Aidan, Alex Bagi, et al. "Abstract P384: Distinct Roles Of Cellular And Extracellular TRNA-derived Small RNAs In Myocardial Fibrosis." Circulation Research 129, Suppl_1 (2021). http://dx.doi.org/10.1161/res.129.suppl_1.p384.
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Heart failure (HF) remains the leading cause of morbidity and mortality in the US, affecting approximately 6.2 million Americans with an anticipated 46% increase in overall prevalence by 2030. Myocardial fibrosis, defined as increased cardiac fibroblast (CF) activation and excessive extracellular matrix (ECM) deposition, is a leading contributor to the progression of adverse heart remodeling that leads to HF. Despite this clinical importance, no FDA-approved antifibrotic drug is available to prevent the development of HF. There is therefore an urgent need to understand pathways important in myocardial fibrosis that can be targeted with novel therapies. Non-coding RNAs, particularly miRNAs and lincRNAs, have emerged as promising novel biomarkers or therapeutic targets for myocardial fibrosis. As an emerging category of small regulatory non-coding RNAs that was discovered only a decade ago, tRNA-derived small RNAs (tDRs), have been shown to play important roles in cancer and neurological disorders. However, the knowledge of tDRs in myocardial remodeling remains scarce. Here, by using a recently developed tDR sequencing technique, called ARM-seq, we have discovered the unique extracellular tDR fragmentation profile and created an atlas of stress-specific cellular and extracellular tDR signatures in both CFs and cardiomyocytes (CMs). Notably, we identified a nutritional deprivation-induced cellular tRNA-Asp-GTC-3’tDR (cl-tRNA-Asp-GTC-3’tDR) that demonstrates potent antifibrotic effects. In vitro mechanistic studies and transcriptome analysis suggest that the lysosome-localized cl-tRNA-Asp-GTC-3’tDR inhibits CF activation through targeting ECM deposition program and cellular response to TGFβ stimulus and the G-quadruplex motifs are required for its functionality. Meanwhile, a related extracellular tDR derived from the same canonical tRNA, ex-tRNA-Asp-GTC-3’tDR, which has two additional nucleotides at both 5’ and 3’ end of cl-tRNA-Asp-GTC-3’tDR, is specifically enriched in the extracellular vesicles derived from CFs and CMs. Our pilot data suggest that the secretion of ex-tRNA-Asp-GTC-3’tDR may be required for maintaining the homeostasis of CFs and CMs. Importantly, we found that cardiac ischemia significantly decreases the circulating ex-tRNA-Asp-GTC-3’tDR level in both cell culture models and human patients during cardiopulmonary bypass surgery or following acute coronary syndrome. Together, our findings identify a cellular tDR that represents an attractive therapeutic target against myocardial fibrosis and an extracellular tDR with the same origin that has a distinct function and may be translated into novel biomarkers for cardiac ischemia.
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Zhou, Yun, Qingxiao Hong, Wenjin Xu, et al. "Differential expression profiling of tRNA-Derived small RNAs and their potential roles in methamphetamine self-administered rats." Frontiers in Genetics 14 (February 2, 2023). http://dx.doi.org/10.3389/fgene.2023.1088498.
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Transfer RNA-derived small RNAs (tsRNAs) are a novel class of short, non-coding RNAs that are closely associated with the pathogenesis of various diseases. Accumulating evidence has demonstrated their critical functional roles as regulatory factors in gene expression regulation, protein translation regulation, regulation of various cellular activities, immune mediation, and response to stress. However, the underlying mechanisms by which tRFs &amp; tiRNAs affect methamphetamine-induced pathophysiological processes are largely unknown. In this study, we used a combination of small RNA sequencing, quantitative reverse transcription-polymerase chain reaction (qRT‒PCR), bioinformatics, and luciferase reporter assays to screen the expression profiles and identify the functional roles of tRFs and tiRNAs in the nucleus accumbens (NAc) of methamphetamine self-administration rat models. A total of 461 tRFs &amp; tiRNAs were identified in the NAc of rats after 14 days of methamphetamine self-administration training. Of those, 132 tRFs &amp; tiRNAs were significantly differentially expressed: 59 were significantly upregulated, whereas 73 were significantly downregulated in the rats with methamphetamine self-administration. Decreased expression levels of tiRNA-1-34-Lys-CTT-1 and tRF-1-32-Gly-GCC-2-M2, as well as increased expression levels of tRF-1-16-Ala-TGC-4 in the METH group compared with the saline control were validated by using RT‒PCR. Then, bioinformatic analysis was performed to analyse the possible biological functions of tRFs &amp; tiRNAs in methamphetamine-induced pathogenesis. Furthermore, tRF-1-32-Gly-GCC-2-M2 was identified to target BDNF using the luciferase reporter assay. An altered tsRNA expression pattern was proven, and tRF-1-32-Gly-GCC-2-M2 was shown to be involved in methamphetamine-induced pathophysiologic processes by targeting BDNF. The current study provides new insights for future investigations to explore the mechanisms and therapeutic methods for methamphetamine addiction.
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Zhou, Yongqiang, Jinjing Hu, Lu Liu, et al. "Gly-tRF enhances LCSC-like properties and promotes HCC cells migration by targeting NDFIP2." Cancer Cell International 21, no. 1 (2021). http://dx.doi.org/10.1186/s12935-021-02102-8.
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Abstract Background Accumulating evidence demonstrates that tRFs (tRNA-derived small RNA fragments) and tiRNAs (tRNA-derived stress-induced RNA), an emerging category of regulatory RNA molecules derived from transfer RNAs (tRNAs), are dysregulated in in various human cancer types and play crucial roles. However, their roles and mechanisms in hepatocellular carcinoma (HCC) and liver cancer stem cells (LCSCs) are still unknown. Methods The expression of glycine tRNA-derived fragment (Gly-tRF) was measured by qRT-PCR. Flow cytometric analysis and sphere formation assays were used to determine the properties of LCSCs. Transwell assays and scratch wound assays were performed to detect HCC cell migration. Western blotting was conducted to evaluate the abundance change of Epithelial-mesenchymal transition (EMT)-related proteins. Dual luciferase reporter assays and signalling pathway analysis were performed to explore the underlying mechanism of Gly-tRF functions. Results Gly-tRF was highly expressed in HCC cell lines and tumour tissues. Gly-tRF mimic increased the LCSC subpopulation proportion and LCSC-like cell properties. Gly-tRF mimic promoted HCC cell migration and EMT. Loss of Gly-tRF inhibited HCC cell migration and EMT. Mechanistically, Gly-tRF decreased the level of NDFIP2 mRNA by binding to the NDFIP2 mRNA 3′ UTR. Importantly, overexpression of NDFIP2 weakened the promotive effects of Gly-tRF on LCSC-like cell sphere formation and HCC cell migration. Signalling pathway analysis showed that Gly-tRF increased the abundance of phosphorylated AKT. Conclusions Gly-tRF enhances LCSC-like cell properties and promotes EMT by targeting NDFIP2 and activating the AKT signalling pathway. Gly-tRF plays tumor-promoting role in HCC and may lead to a potential therapeutic target for HCC.
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Xu, Yan, Haidong Zou, Qi Ding та ін. "tiRNA-Val promotes angiogenesis via Sirt1–Hif-1α axis in mice with diabetic retinopathy". Biological Research 55, № 1 (2022). http://dx.doi.org/10.1186/s40659-022-00381-7.
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Abstract Background Diabetic retinopathy (DR) is a specific microvascular complication arising from diabetes, and its pathogenesis is not completely understood. tRNA-derived stress-induced RNAs (tiRNAs), a new type of small noncoding RNA generated by specific cleavage of tRNAs, has become a promising target for several diseases. However, the regulatory function of tiRNAs in DR and its detailed mechanism remain unknown. Results Here, we analyzed the tiRNA profiles of normal and DR retinal tissues. The expression level of tiRNA-Val was significantly upregulated in DR retinal tissues. Consistently, tiRNA-Val was upregulated in human retinal microvascular endothelial cells (HRMECs) under high glucose conditions. The overexpression of tiRNA-Val enhanced cell proliferation and inhibited cell apoptosis in HRMECs, but the knockdown of tiRNA-Val decreased cell proliferation and promoted cell apoptosis. Mechanistically, tiRNA-Val, derived from mature tRNA-Val with Ang cleavage, decreased Sirt1 expression level by interacting with sirt1 3'UTR, leading to the accumulation of Hif-1α, a key target for DR. In addition, subretinal injection of adeno-associated virus to knock down tiRNA-Val in DR mice ameliorated the symptoms of DR. Conclusion tiRNA-Val enhance cell proliferation and inhibited cell apoptosis via Sirt1/Hif-1α pathway in HRMECs of DR retinal tissues.
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Zhao, Lian, Wei Chen, and Wan-liang Guo. "Serum tRNA-derived fragments as potential biomarkers in children with acute intussusception." Archives of Medical Science, July 27, 2021. http://dx.doi.org/10.5114/aoms/140491.
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IntroductionIntestinal ischemia–reperfusion injury (I/R) can occur during pediatric intussusception, and any delay in diagnosis or treatment can lead to loss of intestinal viability that requires bowel resection. The aim of the present study was to investigate whether transfer ribonucleic acid (tRNA)–derived fragments (tRFs) can serve as candidate biomarkers for pediatric intussusception.Material and methodsUsing high-throughput sequencing technology, we identified differentially expressed tRFs, and ultimately selected three tRFs to establish a signature as a predictive biomarker of pediatric intussusception. Selection of these three upregulated genes was verified using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). We conducted receiver operator characteristic (ROC) curve analysis to evaluate the predictive accuracy of the selected genes for pediatric intussusception.ResultsWe detected 732 tRFs and tRNA-derived stress-induced RNA (tiRNAs), 1705 micro-RNAs (miRNAs), 52 differentially expressed miRNAs, and 34 differentially expressed tRFs and tiRNAs between patients and controls. Compared with controls, we found 33 upregulated miRNAs, 24 upregulated tRFs and tiRNAs, 19 downregulated miRNAs, and 10 downregulated tRFs and tiRNAs in children with intussusception. Using qPCR, the expression trends of tRF-Leu-TAA-006, tRF-Gln-TTG-033 and tRF-Lys-TTT-028 were consistent with the sequencing results. AUCs of tRF-Leu-TAA-006, tRF-Gln-TTG-033 and tRF-Lys-TTT-028 were 0.984, 0.970 and 0.837, respectively.ConclusionsCirculating tRF-Leu-TAA-006, tRF-Gln-TTG-033 and tRF-Lys-TTT-028 expression might be a novel potential biomarker for diagnosis of pediatric intussusception.
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Ni, Yingchen, Anqi Wu, Jianxin Li, Weidong Zhang, and Youhua Wang. "Evaluation of the serum tRNA-derived fragment tRF-5022B as a potential biomarker for the diagnosis of osteoarthritis." Journal of Orthopaedic Surgery and Research 18, no. 1 (2023). http://dx.doi.org/10.1186/s13018-023-04273-8.
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AbstractOsteoarthritis (OA) is a degenerative disease. It is common in middle-aged and elderly people and is one of the main causes of disability. Currently, the etiology of OA is unclear, and no specific biomarkers for the diagnosis of OA have been identified. Therefore, finding a highly sensitive biomarker is essential for a proper diagnosis.TRNA-derived fragments (tRFs) and tRNA-derived stress-induced RNAs (tiRNAs) are newly discovered classes of noncoding RNAs. tRF has been proven in several studies to have significant associations with tumor diagnosis, making it a promising biomarker in cancer research. However, the diagnostic utility of tRF in OA patients and the correlation between OA progression and trf differential expression have yet to be elaborated. The purpose of this research was to identify tRFs with differential expression in OA to assess their potential as OA biomarkers. To determine the tRF-5022B expression level in this research, real-time fluorescence quantitative PCR has been employed. Agarose gel electrophoresis, Sanger sequencing, and other investigations have been employed for evaluating tRF-5022B's molecular properties. Receiver operating characteristic curve analysis has been utilized for assessing the diagnostic effectiveness of the tRF-5022B. The findings demonstrated that tRF-5022B expression was considerably lower in OA serum. The Kellgren–Lawrence grading scale was shown to correspond with serum expression levels. The ROC curve confirmed that tRF-5022B serum expression levels might differentiate OA cases from healthy individuals and RA patients. According to the aforementioned findings, tRF-5022B may be employed as a novel biomarker for OA diagnosis due to its excellent diagnostic value.
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You, Jianbin, Guoliu Yang, Yi Wu, et al. "Plasma tRF-1:29-Pro-AGG-1-M6 and tRF-55:76-Tyr-GTA-1-M2 as novel diagnostic biomarkers for lung adenocarcinoma." Frontiers in Oncology 12 (September 20, 2022). http://dx.doi.org/10.3389/fonc.2022.991451.
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ObjectiveTRNA-derived fragments (tRFs) and tRNA-derived stress-induced RNAs (tiRNAs) are recognized as novel and potential types of non-coding RNAs (ncRNAs), and several tRF/tiRNA signatures are closely associated with tumor diagnosis. This study aimed to analyze the expression profiles of plasma tRFs/tiRNAs and to clarify their diagnostic value in lung adenocarcinoma (LUAD).MethodsThe differential expression profiles of plasma tRFs/tiRNAs in patients with four patients with early LUAD, four patients with advanced LUAD, and four healthy controls were analyzed using high-throughput sequencing technology. Then, plasma tRFs/tiRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR), and their diagnostic efficiency was appraised by receiver operating characteristic curve analysis. The correlation of candidate plasma tRFs/tiRNAs with clinicopathological features was also analyzed. Finally, bioinformatics analysis was performed to explore and identify the potential biological pathways induced by tRFs/tiRNAs.ResultsThe sequencing results revealed that tRFs/tiRNAs from plasma samples in patients with LUAD were differently expressed, supporting the necessity of exploring their potential as biomarkers. The validation results of qRT-PCR demonstrated that the expression level of tRF-1:29-Pro-AGG-1-M6 was downregulated in LUAD, while that of tRF-55:76-Tyr-GTA-1-M2 was upregulated, which was consistent with the sequencing data. The areas under the receiver operating characteristic curve of tRF-1:29-Pro-AGG-1-M6 and tRF-55:76-Tyr-GTA-1-M2 were 0.882 and 0.896, respectively, which have significant values in the diagnosis of LUAD. The expressions of tRF-1:29-Pro-AGG-1-M6 and tRF-55:76-Tyr-GTA-1-M2 in LUAD were obviously correlated with various clinicopathological features such as tumor–node–metastasis stage, node stage, and the expression levels of carcinoembryonic antigen. In addition, their expression was significantly altered from before to after tumor resection in LUAD patients. The results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses further indicated that tRF-1:29-Pro-AGG-1-M6 and tRF-55:76-Tyr-GTA-1-M2 are widely distributed and apparently enriched in several tumor-related signaling pathways.ConclusionsPlasma tRF-1:29-Pro-AGG-1-M6 and tRF-55:76-Tyr-GTA-1-M2 may be promising components in the development of highly sensitive and non-invasive biomarkers for LUAD diagnosis.
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Wang, Bin, Lin Xia, Dan Zhu, et al. "Paternal High-Fat Diet Altered Sperm 5'tsRNA-Gly-GCC Is Associated With Enhanced Gluconeogenesis in the Offspring." Frontiers in Molecular Biosciences 9 (April 11, 2022). http://dx.doi.org/10.3389/fmolb.2022.857875.
Full textAbstract:
Background: Paternal lifestyle, stress and environmental exposures play a crucial role in the health of offspring and are associated with non-genetic inheritance of acquired traits, however the underlying mechanisms are unclear. In this study, we aimed to find out how the sperm tsRNA involved in paternal high-fat diet induced abnormal gluconeogenesis of F1 offspring, and explore the underlying molecular mechanism of its regulation.Method: We generated a paternal high fat diet (42% kcal fat) model to investigate the mechanism by which paternal diet affects offspring metabolism. Four-week-old C57BL/6J male mice were randomly assigned into two groups to receive either a control diet (CD; 10% kcal fat) or a high-fat (HFD; 42% kcal fat) diet for 10 weeks, and mice from each group were then mated with 8-week-old females with control diet in a 1:2 ratio to generate F1. F0 sperms were isolated and small RNAs was sequenced by high-throughput sequencing. Metabolic phenotypes were examined with both F0 and F1.Results: A significant increase in body weight was observed with HFD-F0 mice at 8 weeks of age as compared to CD mice at the same age. F0 mice showed impaired glucose tolerance (GTT), resistance to insulin tolerance (ITT) and increased pyruvate tolerance (PTT) at 14 weeks. HFD-F1 male mice showed no significant difference in body weight. An increase in PTT was found at 13 weeks of age and no significant changes in GTT and ITT. PEPCK and G6Pase that related to gluconeogenesis increased significantly in the liver of HFD-F1 male mice. Sperm sequencing results showed that 5′tsRNA-Gly-GCC derived from tRNA-Gly-GCC-2 specifically was remarkably upregulated in sperm of HFD F0 mice. Q-PCR further showed that this tsRNA was also increased in the liver of HFD-F1 comparison with CD-F1 mice. In addition, we found that 5′tsRNA-Gly-GCC can regulate Sirt6-FoxO1 pathway and be involved in the gluconeogenesis pathway in liver.Conclusion: 5′tsRNA-Gly-GCC that increased in HFD mice mature sperms can promote gluconeogenesis in liver by regulating Sirt6-FoxO1 pathway, which might represent a potential paternal epigenetic factor mediating the intergenerational inheritance of diet-induced metabolic alteration.