BACKGROUND Acute pancreatitis(AP)is a disease featuring acute inflammation of the pancreas and histological destruction of acinar cells.Approximately 20%of AP patients progress to moderately severe or severe pancreati...BACKGROUND Acute pancreatitis(AP)is a disease featuring acute inflammation of the pancreas and histological destruction of acinar cells.Approximately 20%of AP patients progress to moderately severe or severe pancreatitis,with a case fatality rate of up to 30%.However,a single indicator that can serve as the gold standard for prognostic prediction has not been discovered.Therefore,gaining deeper insights into the underlying mechanism of AP progression and the evolution of the disease and exploring effective biomarkers are important for early diagnosis,progression evaluation,and precise treatment of AP.AIM To determine the regulatory mechanisms of tRNA-derived fragments(tRFs)in AP based on small RNA sequencing and experiments.METHODS Small RNA sequencing and functional enrichment analyses were performed to identify key tRFs and the potential mechanisms in AP.Reverse transcription quantitative polymerase chain reaction(RT-qPCR)was conducted to determine tRF expression.AP cell and mouse models were created to investigate the role of tRF36 in AP progression.Lipase,amylase,and cytokine levels were assayed to examine AP progression.Ferritin expression,reactive oxygen species,malondialdehyde,and ferric ion levels were assayed to evaluate cellular ferroptosis.RNA pull down assays and methylated RNA immunoprecipitation were performed to explore the molecular mechanisms.RESULTS RT-qPCR results showed that tRF36 was significantly upregulated in the serum of AP patients,compared to healthy controls.Functional enrichment analysis indicated that target genes of tRF36 were involved in ferroptosisrelated pathways,including the Hippo signaling pathway and ion transport.Moreover,the occurrence of pancreatic cell ferroptosis was detected in AP cells and mouse models.The results of interference experiments and AP cell models suggested that tRF-36 could promote AP progression through the regulation of ferroptosis.Furthermore,ferroptosis gene microarray,database prediction,and immunoprecipitation suggested that tRF-36 accelerated the progression of AP by recruiting insulin-like growth factor 2 mRNA binding protein 3(IGF2BP3)to the p53 mRNA m6A modification site by binding to IGF2BP3,which enhanced p53 mRNA stability and promoted the ferroptosis of pancreatic follicle cells.CONCLUSION In conclusion,regulation of nuclear pre-mRNA domain-containing protein 1B promoted AP development by regulating the ferroptosis of pancreatic cells,thereby acting as a prospective therapeutic target for AP.In addition,this study provided a basis for understanding the regulatory mechanisms of tRFs in AP.展开更多
Non-coding RNAs(ncRNAs) are a type of RNA that is not translated into proteins. Transfer RNAs(tRNAs), a type of ncRNA, are the second most abundant type of RNA in cells. Recent studies have shown that tRNAs can be cle...Non-coding RNAs(ncRNAs) are a type of RNA that is not translated into proteins. Transfer RNAs(tRNAs), a type of ncRNA, are the second most abundant type of RNA in cells. Recent studies have shown that tRNAs can be cleaved into a heterogeneous population of ncRNAs with lengths of 18–40 nucleotides, known as tRNA-derived small RNAs(tsRNAs). There are two main types of tsRNA, based on their length and the number of cleavage sites that they contain: tRNA-derived fragments and tRNA-derived stress-induced RNAs. These RNA species were first considered to be byproducts of tRNA random cleavage. However, mounting evidence has demonstrated their critical functional roles as regulatory factors in the pathophysiological processes of various diseases, including neurological diseases. However, the underlying mechanisms by which tsRNAs affect specific cellular processes are largely unknown. Therefore, this study comprehensively summarizes the following points:(1) The biogenetics of tsRNA, including their discovery, classification, formation, and the roles of key enzymes.(2) The main biological functions of tsRNA, including its miRNA-like roles in gene expression regulation, protein translation regulation, regulation of various cellular activities, immune mediation, and response to stress.(3) The potential mechanisms of pathophysiological changes in neurological diseases that are regulated by tsRNA, including neurodegeneration and neurotrauma.(4) The identification of the functional diversity of tsRNA may provide valuable information regarding the physiological and pathophysiological mechanisms of neurological disorders, thus providing a new reference for the clinical treatment of neurological diseases. Research into tsRNAs in neurological diseases also has the following challenges: potential function and mechanism studies, how to accurately quantify expression, and the exact relationship between tsRNA and miRNA. These challenges require future research efforts.展开更多
tRNA-derived small RNAs (tsRNAs) are non-coding small RNAs that are producedthrough the precise cleavage of tRNA molecules under specific conditions. tsRNA has multiplefunctions, including inhibiting translation, acti...tRNA-derived small RNAs (tsRNAs) are non-coding small RNAs that are producedthrough the precise cleavage of tRNA molecules under specific conditions. tsRNA has multiplefunctions, including inhibiting translation, acting in association with classical small RNAeffector mechanisms, or acting in conjunction with Argonaute proteins that affect cell proliferation, migration, cycle, and apoptosis. Recent studies have revealed the clinical potential oftsRNAs in numerous diseases. This article aims to provide a comprehensive and up-to-date review of the classification and biological function of tsRNAs in gastrointestinal diseases.Furthermore, this review explores the underlying mechanisms by which tsRNAs are believedto exert their effects in both tumor and non-tumor digestive tract diseases. Therefore, specifictsRNAs prove promising for disease diagnosis, prognosis prediction, and therapeutic interventions as novel biomarkers for digestive tract diseases.展开更多
Liver cancer presents divergent clinical behaviors.There remain opportunities for molecular markers to improve liver cancer diagnosis and prognosis,especially since tRNA-derived small RNAs(tsRNA)have rarely been studi...Liver cancer presents divergent clinical behaviors.There remain opportunities for molecular markers to improve liver cancer diagnosis and prognosis,especially since tRNA-derived small RNAs(tsRNA)have rarely been studied.In this study,a random forests(RF)diagnostic model was built based upon tsRNA profiling of paired tumor and adjacent normal samples and validated by independent validation(IV).A LASSO model was used to developed a seven-tsRNA-based risk score signature for liver cancer prognosis.Model performance was evaluated by a receiver operating characteristic curve(ROC curve)and Precision-Recall curve(PR curve).The five-tsRNA-based RF diagnosis model had area under the receiver operating characteristic curve(AUROC)88%and area under the precision–recall curve(AUPR)87%in the discovery cohort and 87%and 86%in IV-AUROC and IV-AUPR,respectively.The seven-tsRNA-based prognostic model predicts the overall survival of liver cancer patients(Hazard Ratio 2.02,95%CI 1.36–3.00,P<0.001),independent of standard clinicopathological prognostic factors.Moreover,the model successfully categorizes patients into high-low risk groups.Diagnostic and prognostic modeling can be reliably utilized in the diagnosis of liver cancer and high-low risk classification of patients based upon tsRNA characterization.展开更多
Apart from their primordial role in protein synthesis,t RNAs can be cleaved to produce t RNA-derived small RNAs(ts RNAs).The biological functions of ts RNAs in plants remain largely unknown.In this study,we developed ...Apart from their primordial role in protein synthesis,t RNAs can be cleaved to produce t RNA-derived small RNAs(ts RNAs).The biological functions of ts RNAs in plants remain largely unknown.In this study,we developed Rtc B ligation-based small RNA(s RNA)sequencing,a method that captures and distinguishes between 3′-2′,3′-cyclic-phosphate(c P)/phosphate(P)-terminated s RNAs and 3′-OH-terminated s RNAs,and profiled 5′ts RNAs and 5′t RNA halves in Arabidopsis thaliana.We found that Arabidopsis 5′ts RNAs and 5′t RNA halves predominantly contain a c P at the 3′end and require S-like RNase 1(RNS1)and RNS3 for their production.One of the most abundant 5′ts RNAs,5′ts R-Ala,by associating with AGO1,negatively regulates Cytochrome P45071 A13(CYP71 A13)expression and camalexin biosynthesis to repress anti-fungal defense.Interestingly,5′ts R-Ala is downregulated upon fungal infection.Our study provides a global view of 5′ts RNAs and 5′t RNA halves in Arabidopsis and unravels an important role of a 5′ts RNA in regulating anti-fungal defense.展开更多
tRNA-derived small RNAs(tsRNAs)are novel non-coding RNAs that are involved in the occurrence and progression of diverse diseases.However,their exact presence and function in hepatocellular carcinoma(HCC)remain unclear...tRNA-derived small RNAs(tsRNAs)are novel non-coding RNAs that are involved in the occurrence and progression of diverse diseases.However,their exact presence and function in hepatocellular carcinoma(HCC)remain unclear.Here,differentially expressed tsRNAs in HCC were profiled.A novel tsRNA,tRNAGln-TTG derived 5′-tiRNA-Gln,is significantly downregulated,and its expression level is correlated with progression in patients.In HCC cells,5′-tiRNA-Gln overexpression impaired the proliferation,migration,and invasion in vitro and in vivo,while 5′-tiRNA-Gln knockdown yielded opposite results.5′-tiRNA-Gln exerted its function by binding eukaryotic initiation factor 4A-I(EIF4A1),which unwinds complex RNA secondary structures during translation initiation,causing the partial inhibition of translation.The suppressed downregulated proteins include ARAF,MEK1/2 and STAT3,causing the impaired signaling pathway related to HCC progression.Furthermore,based on the construction of a mutant 5′-tiRNA-Gln,the sequence of forming intramolecular G-quadruplex structure is crucial for 5′-tiRNA-Gln to strongly bind EIF4A1 and repress translation.Clinically,5′-tiRNA-Gln expression level is negatively correlated with ARAF,MEK1/2,and STAT3 in HCC tissues.Collectively,these findings reveal that 5′-tiRNA-Gln interacts with EIF4A1 to reduce related mRNA binding through the intramolecular Gquadruplex structure,and this process partially inhibits translation and HCC progression.展开更多
基金the National Natural Science Foundation of China,No.81860424.
文摘BACKGROUND Acute pancreatitis(AP)is a disease featuring acute inflammation of the pancreas and histological destruction of acinar cells.Approximately 20%of AP patients progress to moderately severe or severe pancreatitis,with a case fatality rate of up to 30%.However,a single indicator that can serve as the gold standard for prognostic prediction has not been discovered.Therefore,gaining deeper insights into the underlying mechanism of AP progression and the evolution of the disease and exploring effective biomarkers are important for early diagnosis,progression evaluation,and precise treatment of AP.AIM To determine the regulatory mechanisms of tRNA-derived fragments(tRFs)in AP based on small RNA sequencing and experiments.METHODS Small RNA sequencing and functional enrichment analyses were performed to identify key tRFs and the potential mechanisms in AP.Reverse transcription quantitative polymerase chain reaction(RT-qPCR)was conducted to determine tRF expression.AP cell and mouse models were created to investigate the role of tRF36 in AP progression.Lipase,amylase,and cytokine levels were assayed to examine AP progression.Ferritin expression,reactive oxygen species,malondialdehyde,and ferric ion levels were assayed to evaluate cellular ferroptosis.RNA pull down assays and methylated RNA immunoprecipitation were performed to explore the molecular mechanisms.RESULTS RT-qPCR results showed that tRF36 was significantly upregulated in the serum of AP patients,compared to healthy controls.Functional enrichment analysis indicated that target genes of tRF36 were involved in ferroptosisrelated pathways,including the Hippo signaling pathway and ion transport.Moreover,the occurrence of pancreatic cell ferroptosis was detected in AP cells and mouse models.The results of interference experiments and AP cell models suggested that tRF-36 could promote AP progression through the regulation of ferroptosis.Furthermore,ferroptosis gene microarray,database prediction,and immunoprecipitation suggested that tRF-36 accelerated the progression of AP by recruiting insulin-like growth factor 2 mRNA binding protein 3(IGF2BP3)to the p53 mRNA m6A modification site by binding to IGF2BP3,which enhanced p53 mRNA stability and promoted the ferroptosis of pancreatic follicle cells.CONCLUSION In conclusion,regulation of nuclear pre-mRNA domain-containing protein 1B promoted AP development by regulating the ferroptosis of pancreatic cells,thereby acting as a prospective therapeutic target for AP.In addition,this study provided a basis for understanding the regulatory mechanisms of tRFs in AP.
基金supported by the National Natural Science Foundation of China,No.81870979(to JJL),No.81271366(to MLY)the National Key R&D Program of China,No.2018YFF0301104(to JJL)+4 种基金the Special Fund for Basic Scientific Research of Central Public Research Institutes of China,No.2018CZ-1(to JJL)the Basic Scientific Research Foundation of China Rehabilitation Research Center,No.2018ZX-30(to FG)the Scientific Research Foundation of CRRC,No.2012C-1(to JJL)the Major Science and Technology Project of Beijing of China,No.D161100002816004(to JJL)the Special Capital Health Research and Development of China,No.2018-1-6011(to JJL)
文摘Non-coding RNAs(ncRNAs) are a type of RNA that is not translated into proteins. Transfer RNAs(tRNAs), a type of ncRNA, are the second most abundant type of RNA in cells. Recent studies have shown that tRNAs can be cleaved into a heterogeneous population of ncRNAs with lengths of 18–40 nucleotides, known as tRNA-derived small RNAs(tsRNAs). There are two main types of tsRNA, based on their length and the number of cleavage sites that they contain: tRNA-derived fragments and tRNA-derived stress-induced RNAs. These RNA species were first considered to be byproducts of tRNA random cleavage. However, mounting evidence has demonstrated their critical functional roles as regulatory factors in the pathophysiological processes of various diseases, including neurological diseases. However, the underlying mechanisms by which tsRNAs affect specific cellular processes are largely unknown. Therefore, this study comprehensively summarizes the following points:(1) The biogenetics of tsRNA, including their discovery, classification, formation, and the roles of key enzymes.(2) The main biological functions of tsRNA, including its miRNA-like roles in gene expression regulation, protein translation regulation, regulation of various cellular activities, immune mediation, and response to stress.(3) The potential mechanisms of pathophysiological changes in neurological diseases that are regulated by tsRNA, including neurodegeneration and neurotrauma.(4) The identification of the functional diversity of tsRNA may provide valuable information regarding the physiological and pathophysiological mechanisms of neurological disorders, thus providing a new reference for the clinical treatment of neurological diseases. Research into tsRNAs in neurological diseases also has the following challenges: potential function and mechanism studies, how to accurately quantify expression, and the exact relationship between tsRNA and miRNA. These challenges require future research efforts.
基金supported by the National Natural Science Foundation of China(No.82073047,82272995)Guangdong Provincial Basic and Applied Basic Research Foundation Natural Science Foundation(China)(No.2022A1515010954).
文摘tRNA-derived small RNAs (tsRNAs) are non-coding small RNAs that are producedthrough the precise cleavage of tRNA molecules under specific conditions. tsRNA has multiplefunctions, including inhibiting translation, acting in association with classical small RNAeffector mechanisms, or acting in conjunction with Argonaute proteins that affect cell proliferation, migration, cycle, and apoptosis. Recent studies have revealed the clinical potential oftsRNAs in numerous diseases. This article aims to provide a comprehensive and up-to-date review of the classification and biological function of tsRNAs in gastrointestinal diseases.Furthermore, this review explores the underlying mechanisms by which tsRNAs are believedto exert their effects in both tumor and non-tumor digestive tract diseases. Therefore, specifictsRNAs prove promising for disease diagnosis, prognosis prediction, and therapeutic interventions as novel biomarkers for digestive tract diseases.
基金This work was also supported by the NIH Grants(No.5P30GM114737,P20GM103466,U54MD007584 and 2U54MD007601)Natural Science Foundation of Hubei Province(No.2019CFB417).
文摘Liver cancer presents divergent clinical behaviors.There remain opportunities for molecular markers to improve liver cancer diagnosis and prognosis,especially since tRNA-derived small RNAs(tsRNA)have rarely been studied.In this study,a random forests(RF)diagnostic model was built based upon tsRNA profiling of paired tumor and adjacent normal samples and validated by independent validation(IV).A LASSO model was used to developed a seven-tsRNA-based risk score signature for liver cancer prognosis.Model performance was evaluated by a receiver operating characteristic curve(ROC curve)and Precision-Recall curve(PR curve).The five-tsRNA-based RF diagnosis model had area under the receiver operating characteristic curve(AUROC)88%and area under the precision–recall curve(AUPR)87%in the discovery cohort and 87%and 86%in IV-AUROC and IV-AUPR,respectively.The seven-tsRNA-based prognostic model predicts the overall survival of liver cancer patients(Hazard Ratio 2.02,95%CI 1.36–3.00,P<0.001),independent of standard clinicopathological prognostic factors.Moreover,the model successfully categorizes patients into high-low risk groups.Diagnostic and prognostic modeling can be reliably utilized in the diagnosis of liver cancer and high-low risk classification of patients based upon tsRNA characterization.
基金supported by the National Natural Science Foundation of China(31801074,31788103)。
文摘Apart from their primordial role in protein synthesis,t RNAs can be cleaved to produce t RNA-derived small RNAs(ts RNAs).The biological functions of ts RNAs in plants remain largely unknown.In this study,we developed Rtc B ligation-based small RNA(s RNA)sequencing,a method that captures and distinguishes between 3′-2′,3′-cyclic-phosphate(c P)/phosphate(P)-terminated s RNAs and 3′-OH-terminated s RNAs,and profiled 5′ts RNAs and 5′t RNA halves in Arabidopsis thaliana.We found that Arabidopsis 5′ts RNAs and 5′t RNA halves predominantly contain a c P at the 3′end and require S-like RNase 1(RNS1)and RNS3 for their production.One of the most abundant 5′ts RNAs,5′ts R-Ala,by associating with AGO1,negatively regulates Cytochrome P45071 A13(CYP71 A13)expression and camalexin biosynthesis to repress anti-fungal defense.Interestingly,5′ts R-Ala is downregulated upon fungal infection.Our study provides a global view of 5′ts RNAs and 5′t RNA halves in Arabidopsis and unravels an important role of a 5′ts RNA in regulating anti-fungal defense.
基金generously supported by the National Natural Science Foundation of China(Nos.82072650 and 81902405)Key Research and Development Program of Zhejiang Province(No.2021C03121)+1 种基金2019 Liver Cancer Diagnosis and Treatment Communication Fund(No.CXPJJH11900009-12)Grant from Health Commission of Zhejiang Province(No.JBZX-202004).
文摘tRNA-derived small RNAs(tsRNAs)are novel non-coding RNAs that are involved in the occurrence and progression of diverse diseases.However,their exact presence and function in hepatocellular carcinoma(HCC)remain unclear.Here,differentially expressed tsRNAs in HCC were profiled.A novel tsRNA,tRNAGln-TTG derived 5′-tiRNA-Gln,is significantly downregulated,and its expression level is correlated with progression in patients.In HCC cells,5′-tiRNA-Gln overexpression impaired the proliferation,migration,and invasion in vitro and in vivo,while 5′-tiRNA-Gln knockdown yielded opposite results.5′-tiRNA-Gln exerted its function by binding eukaryotic initiation factor 4A-I(EIF4A1),which unwinds complex RNA secondary structures during translation initiation,causing the partial inhibition of translation.The suppressed downregulated proteins include ARAF,MEK1/2 and STAT3,causing the impaired signaling pathway related to HCC progression.Furthermore,based on the construction of a mutant 5′-tiRNA-Gln,the sequence of forming intramolecular G-quadruplex structure is crucial for 5′-tiRNA-Gln to strongly bind EIF4A1 and repress translation.Clinically,5′-tiRNA-Gln expression level is negatively correlated with ARAF,MEK1/2,and STAT3 in HCC tissues.Collectively,these findings reveal that 5′-tiRNA-Gln interacts with EIF4A1 to reduce related mRNA binding through the intramolecular Gquadruplex structure,and this process partially inhibits translation and HCC progression.
