RNA modifications play vital regulatory roles in biological systems.Dysregulated RNA modifications themselves or their regulators are associated with various diseases,including cancers and immune related diseases.Howe...RNA modifications play vital regulatory roles in biological systems.Dysregulated RNA modifications themselves or their regulators are associated with various diseases,including cancers and immune related diseases.However,to the best of our knowledge,RNA modifications in peripheral white blood cells(immune cells)have not been systematically investigated before.Here we utilized hydrophilic interaction liquid chromatography-tandem mass spectrometry(HILIC-MS/MS)for the quantification of 19 chemical modifications in total RNA and 17 chemical modifications in small RNA in peripheral white blood cells from breast cancer patients and healthy controls.We found out 13 RNA modifications were up-regulated in total RNA samples of breast cancer patients.For small RNA samples,only N6-methyladenosine(m^(6)A)was down-regulated in breast cancer patients(P<0.0001).Receiver operating characteristic(ROC)curves analysis showed that N4-acetylcytidine(ac^(4)C)in total RNA had an area under curve(AUC)value of 0.833,and m^(6)A in small RNA had an AUC value of 0.994.Our results further illustrated that RNA modifications may play vital roles in immune cell biology of breast cancer,and may act as novel biomarkers for the diagnosis of breast cancer.展开更多
The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms.Methylation of N6 adenosine(m^(6)A)and C5 cytosine(m^(5)C)bases occur on mRNA...The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms.Methylation of N6 adenosine(m^(6)A)and C5 cytosine(m^(5)C)bases occur on mRNAs,tRNA,mt-tRNA,and rRNA species as well as non-coding RNAs.With emerging knowledge of RNA binding proteins that act as writer,reader,and eraser effector proteins,comes a new understanding of physiological processes controlled by these systems.Such processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain,give rise to different forms of disease.In this review,we discuss accumulating evidence that changes in the m^(6)A and m^(5)C methylation systems contribute to neurocognitive disorders.Early studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m^(6)A RNA reader protein.Subsequently,familial mutations within the m^(6)A writer gene METTL5,m^(5)C writer genes NSUN2,NSUN3,NSUN5,and NSUN6,as well as THOC2 and THOC6 that form a protein complex with the m^(5)C reader protein ALYREF,were recognized to cause intellectual development disorders.Similarly,differences in expression of the m^(5)C writer and reader effector proteins,NSUN6,NSUN7,and ALYREF in brain tissue are indicated in individuals with Alzheimer's disease,individuals with a high neuropathological load or have suffered traumatic brain injury.Likewise,an abundance of m^(6)A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases,Alzheimer's disease,and individuals with high cognitive reserve.m^(6)A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson's disease tissue,whilst modified RNAs are misplaced within diseased cells,particularly where synapses are located.In parahippocampal brain tissue,m^(6)A modification is enriched in transcripts associated with psychiatric disorders including conditions with clear cognitive deficits.These findings indicate a diverse set of molecular mechanisms are influenced by RNA methylation systems that can cause neuronal and synaptic dysfunction underlying neurocognitive disorders.Targeting these RNA modification systems brings new prospects for neural regenerative therapies.展开更多
Alcohol consumption is one of the leading causes of death worldwide.Adolescence is a critical period of structural and functional maturation of the brain.Adolescent alcohol use can alter epigenetic modifications.Howev...Alcohol consumption is one of the leading causes of death worldwide.Adolescence is a critical period of structural and functional maturation of the brain.Adolescent alcohol use can alter epigenetic modifications.However,little is known on the long-term effects of alcohol consumption during adolescence on RNA epigenetic modifications in brain.Herein,we systematically explored the long-term effects of alcohol exposure during adolescence on small RNA modifications in adult rat brain tissues by comprehensive liquid chromatography-electrospray ionization-tandem mass spectrometry(LC-ESI-MS/MS)analysis.We totally detected 26 modifications in small RNA of brain tissues.Notably,we observed most of these modifications were decreased in brain tissues.These results suggest that alcohol exposure during adolescence may impose a long-lasting impact on RNA modifications in brain tissues.This is the first report that alcohol use during adolescence can alter RNA modifications in adult brain.Collectively,this study suggests a long-term adverse effects of alcohol consumption on brain from RNA epigenetics angle by comprehensive mass spectrometry analysis.展开更多
Sleep deprivation(SD)is a widespread issue that disrupts the lives of millions of people.These effects ini-tiate as changes within neurons,specifically at the DNA and RNA level,leading to disruptions in neuronal plast...Sleep deprivation(SD)is a widespread issue that disrupts the lives of millions of people.These effects ini-tiate as changes within neurons,specifically at the DNA and RNA level,leading to disruptions in neuronal plasticity and the dysregulation of various cognitive functions,such as learning and memory.Nucleic acid epigenetic modifications that could regulate gene expression have been reported to play crucial roles in this process.However,there is a lack of comprehensive research on the correlation of SD with nucleic acid epigenetic modifications.In the current study,we aimed to systematically investigate the landscape of modifications in DNA as well as in small RNA molecules across multiple tissues,including the heart,liver,kidney,lung,hippocampus,and spleen,in response to chronic sleep deprivation(CSD).Using liquid chromatography-tandem mass spectrometry(LC-MS/MS)analysis,we characterized the dynamic changes in DNA and RNA modification profiles in different tissues of mice under CSD stress.Specifically,we ob-served a significant decrease in the level of 5-methylcytosine(5mC)and a significant increase in the level of 5-hydroxymethylcytosine(5hmC)in the kidney in CSD group.Regarding RNA modifications,we observed an overall increased trend for most of these significantly changed modifications across six tis-sues in CSD group.Our study sheds light on the significance of DNA and RNA modifications as crucial epigenetic markers in the context of CSD-induced stress.展开更多
Inosine is a vital RNA modification across three kingdoms of life.It has been demonstrated that inosine plays important roles in modulation of the fate of RNAs.In the current study,we developed a highly sensitive meth...Inosine is a vital RNA modification across three kingdoms of life.It has been demonstrated that inosine plays important roles in modulation of the fate of RNAs.In the current study,we developed a highly sensitive method to determine inosine in a single cell by N-cyclohexyl-N’-β-(4-methylmorpholinium)ethylcarbodiimide p-toluenesulfonate(CMCT)derivatization in combination with mass spectrometry analysis.The results showed that the detection sensitivity of inosine was increased by 556-fold after CMCT derivatization,with the limit of detection(LOD)being 4.5 amol.With the established method,we could detect inosine from 13.0 pg of total RNA of HEK293T cells.Meanwhile,inosine in RNA from a single cell could also be clearly detected due to the improved detection sensitivity.Moreover,we found the level of inosine in RNA of sleep-deprived mice was significantly increased compared to the control mice,indicating that inosine is associated with sleep behavior and might be a potential indicator of sleep disorder.Taken together,the chemical derivatization coupled with mass spectrometry analysis offers a valuable tool in determination of endogenous RNA modifications in a single cell,which should benefit the functional study of RNA modification in rare clinical samples.展开更多
Alcohol consumption is a critical risk factor contributing to a verity of human diseases. The incidence of alcohol use disorder increases across adolescence in recent years. Accumulating line of evidence suggests that...Alcohol consumption is a critical risk factor contributing to a verity of human diseases. The incidence of alcohol use disorder increases across adolescence in recent years. Accumulating line of evidence suggests that alcohol-induced changes of DNA cytosine methylation(5-methyl-2-deoxycytidine, 5 m C) in genomes play an important role in the development of diseases. However, systemic investigation of the effects of adolescent alcohol exposure on DNA and RNA modifications is still lacked. Especially, there hasn’t been any report to study the effects of alcohol exposure on RNA modifications. Similar to DNA modifications,RNA modifications recently have been identified to function as new regulators in modulating numbers of biological processes. In the current study, we systematically investigated the effects of alcohol exposure on both DNA and RNA modifications in peripheral blood of adolescent rats by liquid chromatographyelectrospray ionization-tandem mass spectrometry(LC-ESI-MS/MS) analysis. The developed LC-ESI-MS/MS method enabled the sensitive and accurate determination of 2 DNA modifications and 12 RNA modifications. As for the alcohol exposure experiments, the adolescent rats were intraperitoneally injected with ethanol with an interval of one day for a total 14 days. The quantification results by LC-ESI-MS/MS analysis showed that adolescent alcohol exposure could alter both DNA and RNA modifications in peripheral blood. Specifically, we observed an overall decreased trend of RNA modifications. The discovery of the significant alteration of the levels of DNA and RNA modifications under alcohol exposure indicates that alcohol consumption may increase the risk of the incidence and development of diseases through dysregulating DNA and RNA modifications.展开更多
RNA molecules contain diverse modifications that display important functions in a variety of physiological and pathological processes.So far over 150 chemical modifications have been characterized to be present in var...RNA molecules contain diverse modifications that display important functions in a variety of physiological and pathological processes.So far over 150 chemical modifications have been characterized to be present in various RNA species,such as in messenger RNA(mRNA),ribosomal RNA(rRNA),and transfer RNA(tRNA).Previous studies revealed that certain RNA modifications were correlated to specific human diseases,indicating RNA modifications could serve as the potential indicator of human diseases.However,systemic investigation of the alteration of RNA modifications in different RNA species of carcinoma tissues are still lacked.Herein,we carried out the comprehensive profiling and evaluation of the alteration of RNA modifications in thyroid carcinoma by liquid chromatography-tandem mass spectrometry(LC-ESIMS/MS)analysis.The developed method allowed us to simultaneously detect 48 different types of RNA modifications.Using this method,we detected 10,15,14,and 25 modifications in m RNA,18 S r RNA,28 S rRNA and small RNA(<200 nt),respectively.Compared to the normal tissues,we revealed a total of 14 RNA modification exhibited significant increase and 2 RNA modifications showed significant decrease in thyroid carcinoma tissues.Our study provided the first comprehensive profile as well as the alteration of modifications in different RNA species in thyroid carcinoma and matched tumor-adjacent normal tissues.The altered pattern RNA modifications may serve as the indicator of thyroid carcinoma.Moreover,this study may promote the in-depth understanding of the regulatory roles of RNA modifications in thyroid carcinoma.展开更多
N6-methyladenosine(M6A)is the most common modification in eukaryotic RNAs for the regulation of RNA transcription,processing,splicing,degradation,and translation.RNA modification by M6A is dynamically reversible,invol...N6-methyladenosine(M6A)is the most common modification in eukaryotic RNAs for the regulation of RNA transcription,processing,splicing,degradation,and translation.RNA modification by M6A is dynamically reversible,involving methylated transferase,demethylase,and methylated reading protein.M6A-mediated gene regulation involves cell differentiation,metastasis,apoptosis,and proliferation.Dysregulation of M6A can lead to various diseases.Cardiovascular disease(CVD)seriously endangers human health and brings great social burden.Seeking effective prevention and treatment strategies for CVD is a challenge to both fundamentalists and clinicians.Substantial evidence has suggested the key role of M6A modification in the development of CVDs.This review summarizes the mechanism of M6A RNA modification and the latest research progress in respect with its role in CVDs,including atherosclerosis,coronary artery disease,myocardial infarction and cardiac remodeling,myocardial ischemia-reperfusion injury,heart failure,hypertension,and aortic aneurysm,and the potential applications of the findings to CVDs,thereby providing new ideas and approaches for the diagnosis and therapy of CVDs.展开更多
Epitranscriptomic chemical modifications of RNAs have emerged as potent regulatory mechanisms in the process of plant stress adaptation.Currently,over 170 distinct chemical modifications have been identified in mRNAs,...Epitranscriptomic chemical modifications of RNAs have emerged as potent regulatory mechanisms in the process of plant stress adaptation.Currently,over 170 distinct chemical modifications have been identified in mRNAs,tRNAs,rRNAs,microRNAs(miRNAs),and long noncoding RNAs(lncRNAs).Genetic and molec-ular studies have identified the genes responsible for addition and removal of chemical modifications from RNA molecules,which are known as"writers"and"erasers,"respectively.N^(6)-methyladenosine(m^(6)A)is the most prevalent chemical modification identified in eukaryotic mRNAs.Recent studies have identified m6 A writers and erasers across different plant species,including Arabidopsis(Arabidopsis thaliana),rice(Oryza sativa),cotton(Gossypium hirsutum),and tomato(Solanum lycopersicum).Accumulating discoveries have improved our understanding of the functions of RNA modifications in plant stress responses.This review highlights the latest research on RNA modification,emphasizing the biological and cellular roles of diverse chemical modifications of mRNAs,tRNAs,rRNAs,miRNAs,and lncRNAs in plant responses to environ-mental and hormonal signals.We also propose and discuss critical questions and future challenges for enhancing our understanding of the cellular and mechanistic roles of RNA modifications in plant stress re-sponses.Integrating molecular insights into the regulatory roles of RNA modifications in stress responses with novel genome-and RNA-editing technologies will facilitate the breeding of stress-tolerant crops through precise engineering of RNA modifications.展开更多
The chemical modifications of DNA and proteins are powerful mechanisms for regulating molecular and biological functions,influencing a wide array of signaling pathways in eukaryotes.Recent advance-ments in epitranscri...The chemical modifications of DNA and proteins are powerful mechanisms for regulating molecular and biological functions,influencing a wide array of signaling pathways in eukaryotes.Recent advance-ments in epitranscriptomics have shown that RNA modifications play crucial roles in diverse biological processes.Since their discovery in the 1970s,scientists have sought to decipher,identify,and elucidate the functions of these modifications across biological systems.Over the past decade,mounting evi-dence has demonstrated the importance of RNA modification pathways in plants,prompting significant efforts to decipher their physiological relevance.With the advent of high-resolution mapping tech-niques for RNA modifications and the gradual uncovering of their biological roles,our understanding of this additional layer of regulation is beginning to take shape.In this review,we summarize recent findings on the major RNA modifications identified in plants,with an emphasis on N^(6)-methyladenosine(m^(6)A),the most extensively studied modification.We discuss the functional signifi-cance of the effector components involved in m^(6)A modification and its diverse roles in plant biotic in-teractions,including plant–virus,plant–bacterium,plant–fungus,and plant–insect relationships.Furthermore,we highlight new technological developments driving research progress in this field and outline key challenges that remain to be addressed.展开更多
RNA modifications greatly expand the functional diversity of RNA molecules,impacting RNA's stability,folding,and interactions with other biomolecules.These modifications play critical roles in cellular processes a...RNA modifications greatly expand the functional diversity of RNA molecules,impacting RNA's stability,folding,and interactions with other biomolecules.These modifications play critical roles in cellular processes and are increasingly linked to disease states.Developments in mass spectrometry(MS),nuclear magnetic resonance(NMR),and chemical probing techniques have provided insights into the mechanisms and functions of RNA modifications.Combining these experimental approaches allows researchers to explore the complexities of RNA modifications and their effects on RNA structure and dynamics.This review highlights recent progresses in the field and examines how the integration of MS,NMR,and complementary techniques is advancing our understanding of RNA modifications and their biological significance.展开更多
Non-alcoholic fatty liver disease(NAFLD)has emerged as a prominent global health concern associated with high risk of metabolic syndrome,and has impacted a substantial segment of the population.The disease spectrum ra...Non-alcoholic fatty liver disease(NAFLD)has emerged as a prominent global health concern associated with high risk of metabolic syndrome,and has impacted a substantial segment of the population.The disease spectrum ranges from simple fatty liver to non-alcoholic steatohepatitis(NASH),which can progress to cirrhosis and hepatocellular carcinoma(HCC)and is increasingly becoming a prevalent indication for liver transplantation.The existing therapeutic options for NAFLD,NASH,and HCC are limited,underscoring the urgent need for innovative treatment strategies.Insights into gene expression,particularly RNA modifications such as N6methyladenosine(m^(6)A),hold promising avenues for interventions.These modifications play integral roles in RNA metabolism and cellular functions,encompassing the entire NAFLD-NASH-HCC progression.This review will encompass recent insights on diverse RNA modifications,including m^(6)A,pseudouridine(Ψ),N^(1)-methyladenosine(m^(1)A),and 5-methylcytidine(m^(5)C)across various RNA species.It will uncover their significance in crucial aspects such as steatosis,inflammation,fibrosis,and tumorigenesis.Furthermore,prospective research directions and therapeutic implications will be explored,advancing our comprehensive understanding of the intricate interconnected nature of these pathological conditions.展开更多
Background Genome-wide association studies(GWAS)have identified more than a thousand loci for blood pressure(BP).Functional genes in these loci are cell-type specific.The aim of this study was to elucidate potentially...Background Genome-wide association studies(GWAS)have identified more than a thousand loci for blood pressure(BP).Functional genes in these loci are cell-type specific.The aim of this study was to elucidate potentially functional genes associated with BP in the aorta through the utilization of RNA modification-associated single-nucleotide polymorphisms(RNAm-SNPs).Methods Utilizing large-scale genetic data of 757,601 individuals from the UK Biobank and International Consortium of Blood Pressure consortium,we identified associations between RNAm-SNPs and BP.The association between RNAm-SNPs,gene expression,and BP were examined.Results A total of 355 RNAm-SNPs related to m6A,m1A,m5C,m7G,and A-to-I modification were associated with BP.The related genes were enriched in the pancreatic secretion pathway and renin secretion pathway.The BP GWAS signals were significantly enriched with m6A-SNPs,highlighting the potential functional relevance of m6A in physiological processes influencing BP.Notably,m6A-SNPs in CYP11B1,PDE3B,HDAC7,ACE,SLC4A7,PDE1A,FRK,MTHFR,NPPA,CACNA1D,and HDAC9 were identified.Differential methylation and differential expression of the BP genes in FTO-overexpression and METTL14-knockdown vascular smooth muscle cells were detected.RNAm-SNPs were associated with ascending and descending aorta diameter and the genes showed differential methylation between aortic dissection(AD)cases and controls.In scRNA-seq study,we identified ARID5A,HLA-DPB1,HLA-DRA,IRF1,LINC01091,MCL1,MLF1,MLXIPL,NAA16,NADK,RERG,SRM,and USP53 as differential expression genes for AD in aortic cells.Conclusion The present study identified RNAm-SNPs in BP loci and elucidated the associations between the RNAm-SNPs,gene expression,and BP.The identified BP-associated genes in aortic cells were associated with AD.展开更多
RNA modification is an essential component of the epitranscriptome,regulating RNA metabolism and cellular functions.Several types of RNA modifications have been identified to date;they include N^(6)-methyladenosine(m^...RNA modification is an essential component of the epitranscriptome,regulating RNA metabolism and cellular functions.Several types of RNA modifications have been identified to date;they include N^(6)-methyladenosine(m^(6)A),N^(1)-methyladenosine(m1A),5-methylcytosine(m5C),N^(7)-methylguanosine(m^(7)G),N^(6),2′-O-dimethyladenosine(m^(6)Am),N4-acetylcytidine(ac^(4)C),etc.RNA modifications,mediated by regulators including writers,erasers,and readers,are associated with carcinogenesis,tumor microenvironment,metabolic reprogramming,immunosuppression,immunotherapy,chemotherapy,etc.A novel perspective indicates that regulatory subunits and post-translational modifications(PTMs)are involved in the regulation of writer,eraser,and reader functions in mediating RNA modifications,tumorigenesis,and anticancer therapy.In this review,we summarize the advances made in the knowledge of different RNA modifications(especially m^(6)A)and focus on RNA modification regulators with functions modulated by a series of factors in cancer,including regulatory subunits(proteins,noncoding RNA or peptides encoded by long noncoding RNA)and PTMs(acetylation,SUMOylation,lactylation,phosphorylation,etc.).We also delineate the relationship between RNA modification regulator functions and carcinogenesis or cancer progression.Additionally,inhibitors that target RNA modification regulators for anticancer therapy and their synergistic effect combined with immunotherapy or chemotherapy are discussed.展开更多
Epitranscriptomics focuses on the RNA-modification-mediated post-transcriptional regulation of gene expression.The past decade has witnessed tremendous progress in our understanding of the landscapes and biological fu...Epitranscriptomics focuses on the RNA-modification-mediated post-transcriptional regulation of gene expression.The past decade has witnessed tremendous progress in our understanding of the landscapes and biological functions of RNA modifications,as prompted by the emergence of potent analytical approaches.The hematopoietic system provides a lifelong supply of blood cells,and gene expression is tightly controlled during the differentiation of hematopoietic stem cells(HSCs).The dysregulation of gene expression during hematopoiesis may lead to severe disorders,including acute myeloid leukemia(AML).Emerging evidence supports the involvement of the mRNA modification system in normal hematopoiesis and AML pathogenesis,which has led to the development of small-molecule inhibitors that target N6-methyladenosine(m^(6)A)modification machinery as treatments.Here,we summarize the latest findings and our most up-to-date information on the roles of m^(6)A and N7-methylguanine in both physiological and pathological conditions in the hematopoietic system.Furthermore,we will discuss the therapeutic potential and limitations of cancer treatments targeting m^(6)A.展开更多
N^(6),2′-O-dimethyladenosine(m^(6)Am)is a prevalent modification frequently found at the 5′cap-adjacent adenosine of messenger RNAs(mRNAs)and small nuclear RNAs(snRNAs)and the internal adenosine of snRNAs.This dynam...N^(6),2′-O-dimethyladenosine(m^(6)Am)is a prevalent modification frequently found at the 5′cap-adjacent adenosine of messenger RNAs(mRNAs)and small nuclear RNAs(snRNAs)and the internal adenosine of snRNAs.This dynamic and reversible modification is under the regulation of methyltransferases phosphorylated CTD interacting factor 1 and methyltransferase-like protein 4,along with the demethylase fat mass and obesity-associated protein.m^(6)Am RNA modification plays a crucial role in the regulation of pre-mRNA splicing,mRNA stability,and translation,thereby influencing gene expression.In recent years,there has been growing interest in exploring the functions of m^(6)Am and its relevance to human diseases.In this review,we provide a comprehensive overview of the current knowledge concerning m^(6)Am,with a focus on m^(6)Am-modifying enzymes,sequencing approaches for its detection,and its impacts on pre-mRNA splicing,mRNA stability,and translation regulation.Furthermore,we highlight the roles of m^(6)Am in the context of obesity,viral infections,and cancers,unravelling its underlying regulatory mechanisms.展开更多
The discovery of glycosylated RNA molecules,known as glycoRNAs,introduces a novel dimension to cellular biology.This commentary explores the transformative findings surrounding glycoRNAs,emphasizing their unique roles...The discovery of glycosylated RNA molecules,known as glycoRNAs,introduces a novel dimension to cellular biology.This commentary explores the transformative findings surrounding glycoRNAs,emphasizing their unique roles in cancer progression and the therapeutic opportunities they present.GlycoRNAs,through interactions with lectins and immune receptors,may contribute to tumor immune evasion.Moreover,the therapeutic potential of this emerging knowledge includes interventions targeting glycoRNA synthesis and modulation of associated signaling pathways.By highlighting these critical insights,this commentary aims to encourage the development of innovative strategies that could improve cancer prognosis and treatment.展开更多
More than 100 modifications have been found in RNA. Analogous to epigenetic DNA methylation, epitranscriptomic modifications can be written, read, and erased by a complex network of proteins. Apart from Na-methyladeno...More than 100 modifications have been found in RNA. Analogous to epigenetic DNA methylation, epitranscriptomic modifications can be written, read, and erased by a complex network of proteins. Apart from Na-methyladenosine （m6A）, N1-methyladenosine （mXA） has been found as a reversible modification in tRNA and mRNA. mlA occurs at positions 9, 14, and 58 of tRNA, with m1A58 being critical for tRNA stability. Other than the hundreds of m1A sites in mRNA and long non-coding RNA transcripts, transcriptome-wide mapping of m1A also identifies 〉 20 m1A sites in mitochondrial genes, m1A in the coding region of mitochondrial transcripts can inhibit the translation of the corresponding proteins. In this review, we summarize the current understanding of mlA in mRNA and tRNA, covering high-throughput sequencing methods developed for m1A methylome, m1A-related enzymes （writers and erasers）, as well as its functions in mRNA and tRNA.展开更多
Ever since the first RNA nucleoside modification was charac- terized in 1957 [1], over 100 distinct chemical modifications have been identified in RNA to date [2]. Most of these modi- fications were characterized in n...Ever since the first RNA nucleoside modification was charac- terized in 1957 [1], over 100 distinct chemical modifications have been identified in RNA to date [2]. Most of these modi- fications were characterized in non-coding RNAs （ncRNAs）, including tRNA, rRNA, and small nuclear RNA （snRNA） [3]. Studies in the past few decades have located various mod- ifications in these ncRNAs and revealed their functional roles [3]. For instance, NLmethyladenosine （mlA）, which is typically found at position 58 in the tRNA T-loop of eukaryotes, func- tions to stabilize tRNA tertiary structure [4] and affect transla- tion by regulating the associations between tRNA and polysome [5]. Pseudouridine （tp） in snRNA can fine-tune branch site interactions and affect mRNA splicing [6].展开更多
Chemical modifications expand the composition of RNA molecules from four standard nucleosides to over 160 modified nucleosides,which greatly increase the complexity and utility of RNAs.Transfer RNAs(tRNAs)are the most...Chemical modifications expand the composition of RNA molecules from four standard nucleosides to over 160 modified nucleosides,which greatly increase the complexity and utility of RNAs.Transfer RNAs(tRNAs)are the most heavily modified cellular RNA molecules and contain the largest variety of modifications.Modification of tRNAs is pivotal for protein synthesis and also precisely regulates the noncanonical functions of tRNAs.Defects in tRNA modifications lead to numerous human diseases.Up to now,more than 100 types of modifications have been found in tRNAs.Intriguingly,some modifications occur widely on all tRNAs,while others only occur on a subgroup of tRNAs or even only a specific tRNA.The modification frequency of each tRNA is approximately 7% to 25%,with 5-20 modification sites present on each tRNA.The occurrence and modulation of tRNA modifications are specifically noticeable as plenty of interplays among different sites and modifications have been discovered.In particular,tRNA modifications are responsive to environmental changes,indicating their dynamic and highly organized nature.In this review,we summarized the known occurrence order,cross-talk,and cooperativity of tRNA modifications.展开更多
基金supported by National Natural Science Foundation of China(Nos.21927810,22336004 and 22176167).
文摘RNA modifications play vital regulatory roles in biological systems.Dysregulated RNA modifications themselves or their regulators are associated with various diseases,including cancers and immune related diseases.However,to the best of our knowledge,RNA modifications in peripheral white blood cells(immune cells)have not been systematically investigated before.Here we utilized hydrophilic interaction liquid chromatography-tandem mass spectrometry(HILIC-MS/MS)for the quantification of 19 chemical modifications in total RNA and 17 chemical modifications in small RNA in peripheral white blood cells from breast cancer patients and healthy controls.We found out 13 RNA modifications were up-regulated in total RNA samples of breast cancer patients.For small RNA samples,only N6-methyladenosine(m^(6)A)was down-regulated in breast cancer patients(P<0.0001).Receiver operating characteristic(ROC)curves analysis showed that N4-acetylcytidine(ac^(4)C)in total RNA had an area under curve(AUC)value of 0.833,and m^(6)A in small RNA had an AUC value of 0.994.Our results further illustrated that RNA modifications may play vital roles in immune cell biology of breast cancer,and may act as novel biomarkers for the diagnosis of breast cancer.
基金funded by Notingham University and the Neuroscience Support Group Charity,UK(to HMK)supported by a CONACYT PhD scholarshipMD?was supported by the Postdoctoral Research Fellowship Program of TUBITAK。
文摘The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms.Methylation of N6 adenosine(m^(6)A)and C5 cytosine(m^(5)C)bases occur on mRNAs,tRNA,mt-tRNA,and rRNA species as well as non-coding RNAs.With emerging knowledge of RNA binding proteins that act as writer,reader,and eraser effector proteins,comes a new understanding of physiological processes controlled by these systems.Such processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain,give rise to different forms of disease.In this review,we discuss accumulating evidence that changes in the m^(6)A and m^(5)C methylation systems contribute to neurocognitive disorders.Early studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m^(6)A RNA reader protein.Subsequently,familial mutations within the m^(6)A writer gene METTL5,m^(5)C writer genes NSUN2,NSUN3,NSUN5,and NSUN6,as well as THOC2 and THOC6 that form a protein complex with the m^(5)C reader protein ALYREF,were recognized to cause intellectual development disorders.Similarly,differences in expression of the m^(5)C writer and reader effector proteins,NSUN6,NSUN7,and ALYREF in brain tissue are indicated in individuals with Alzheimer's disease,individuals with a high neuropathological load or have suffered traumatic brain injury.Likewise,an abundance of m^(6)A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases,Alzheimer's disease,and individuals with high cognitive reserve.m^(6)A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson's disease tissue,whilst modified RNAs are misplaced within diseased cells,particularly where synapses are located.In parahippocampal brain tissue,m^(6)A modification is enriched in transcripts associated with psychiatric disorders including conditions with clear cognitive deficits.These findings indicate a diverse set of molecular mechanisms are influenced by RNA methylation systems that can cause neuronal and synaptic dysfunction underlying neurocognitive disorders.Targeting these RNA modification systems brings new prospects for neural regenerative therapies.
基金the National Key R&D Program of China(Nos.2022YFA0806601,2022YFC3400700)the National Natural Science Foundation of China(Nos.22277093,22074110,21721005)+1 种基金the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University(No.JCRCGW-2022-008)the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(No.ZNJC202208).
文摘Alcohol consumption is one of the leading causes of death worldwide.Adolescence is a critical period of structural and functional maturation of the brain.Adolescent alcohol use can alter epigenetic modifications.However,little is known on the long-term effects of alcohol consumption during adolescence on RNA epigenetic modifications in brain.Herein,we systematically explored the long-term effects of alcohol exposure during adolescence on small RNA modifications in adult rat brain tissues by comprehensive liquid chromatography-electrospray ionization-tandem mass spectrometry(LC-ESI-MS/MS)analysis.We totally detected 26 modifications in small RNA of brain tissues.Notably,we observed most of these modifications were decreased in brain tissues.These results suggest that alcohol exposure during adolescence may impose a long-lasting impact on RNA modifications in brain tissues.This is the first report that alcohol use during adolescence can alter RNA modifications in adult brain.Collectively,this study suggests a long-term adverse effects of alcohol consumption on brain from RNA epigenetics angle by comprehensive mass spectrometry analysis.
基金supported by the National Key R&D Program of China(Nos.2022YFC3400700,2022YFA0806600)the National Natural Science Foundation of China(Nos.22277093,22074110,21721005)+2 种基金the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University(No.JCRCGW-2022-008)the Wuhan Knowledge Innovation Project(No.2022020801010111)the Natural Science Foundation of Hubei Province(No.2022CFB569).
文摘Sleep deprivation(SD)is a widespread issue that disrupts the lives of millions of people.These effects ini-tiate as changes within neurons,specifically at the DNA and RNA level,leading to disruptions in neuronal plasticity and the dysregulation of various cognitive functions,such as learning and memory.Nucleic acid epigenetic modifications that could regulate gene expression have been reported to play crucial roles in this process.However,there is a lack of comprehensive research on the correlation of SD with nucleic acid epigenetic modifications.In the current study,we aimed to systematically investigate the landscape of modifications in DNA as well as in small RNA molecules across multiple tissues,including the heart,liver,kidney,lung,hippocampus,and spleen,in response to chronic sleep deprivation(CSD).Using liquid chromatography-tandem mass spectrometry(LC-MS/MS)analysis,we characterized the dynamic changes in DNA and RNA modification profiles in different tissues of mice under CSD stress.Specifically,we ob-served a significant decrease in the level of 5-methylcytosine(5mC)and a significant increase in the level of 5-hydroxymethylcytosine(5hmC)in the kidney in CSD group.Regarding RNA modifications,we observed an overall increased trend for most of these significantly changed modifications across six tis-sues in CSD group.Our study sheds light on the significance of DNA and RNA modifications as crucial epigenetic markers in the context of CSD-induced stress.
基金supported by the National Key R&D Program of China(Nos.2022YFA0806600,2022YFC3400700)the National Natural Science Foundation of China(Nos.22277093,22074110,21721005).
文摘Inosine is a vital RNA modification across three kingdoms of life.It has been demonstrated that inosine plays important roles in modulation of the fate of RNAs.In the current study,we developed a highly sensitive method to determine inosine in a single cell by N-cyclohexyl-N’-β-(4-methylmorpholinium)ethylcarbodiimide p-toluenesulfonate(CMCT)derivatization in combination with mass spectrometry analysis.The results showed that the detection sensitivity of inosine was increased by 556-fold after CMCT derivatization,with the limit of detection(LOD)being 4.5 amol.With the established method,we could detect inosine from 13.0 pg of total RNA of HEK293T cells.Meanwhile,inosine in RNA from a single cell could also be clearly detected due to the improved detection sensitivity.Moreover,we found the level of inosine in RNA of sleep-deprived mice was significantly increased compared to the control mice,indicating that inosine is associated with sleep behavior and might be a potential indicator of sleep disorder.Taken together,the chemical derivatization coupled with mass spectrometry analysis offers a valuable tool in determination of endogenous RNA modifications in a single cell,which should benefit the functional study of RNA modification in rare clinical samples.
基金supported by the National Natural Science Foundation of China (Nos. 22074110, 21635006, 21721005, 31771193)the Fundamental Research Funds for the Central Universities (No.2042021kf0212)。
文摘Alcohol consumption is a critical risk factor contributing to a verity of human diseases. The incidence of alcohol use disorder increases across adolescence in recent years. Accumulating line of evidence suggests that alcohol-induced changes of DNA cytosine methylation(5-methyl-2-deoxycytidine, 5 m C) in genomes play an important role in the development of diseases. However, systemic investigation of the effects of adolescent alcohol exposure on DNA and RNA modifications is still lacked. Especially, there hasn’t been any report to study the effects of alcohol exposure on RNA modifications. Similar to DNA modifications,RNA modifications recently have been identified to function as new regulators in modulating numbers of biological processes. In the current study, we systematically investigated the effects of alcohol exposure on both DNA and RNA modifications in peripheral blood of adolescent rats by liquid chromatographyelectrospray ionization-tandem mass spectrometry(LC-ESI-MS/MS) analysis. The developed LC-ESI-MS/MS method enabled the sensitive and accurate determination of 2 DNA modifications and 12 RNA modifications. As for the alcohol exposure experiments, the adolescent rats were intraperitoneally injected with ethanol with an interval of one day for a total 14 days. The quantification results by LC-ESI-MS/MS analysis showed that adolescent alcohol exposure could alter both DNA and RNA modifications in peripheral blood. Specifically, we observed an overall decreased trend of RNA modifications. The discovery of the significant alteration of the levels of DNA and RNA modifications under alcohol exposure indicates that alcohol consumption may increase the risk of the incidence and development of diseases through dysregulating DNA and RNA modifications.
基金supported by the National Natural Science Foundation of China(No.22074110)the Fundamental Research Funds for the Central Universities(No.2042021kf0212)。
文摘RNA molecules contain diverse modifications that display important functions in a variety of physiological and pathological processes.So far over 150 chemical modifications have been characterized to be present in various RNA species,such as in messenger RNA(mRNA),ribosomal RNA(rRNA),and transfer RNA(tRNA).Previous studies revealed that certain RNA modifications were correlated to specific human diseases,indicating RNA modifications could serve as the potential indicator of human diseases.However,systemic investigation of the alteration of RNA modifications in different RNA species of carcinoma tissues are still lacked.Herein,we carried out the comprehensive profiling and evaluation of the alteration of RNA modifications in thyroid carcinoma by liquid chromatography-tandem mass spectrometry(LC-ESIMS/MS)analysis.The developed method allowed us to simultaneously detect 48 different types of RNA modifications.Using this method,we detected 10,15,14,and 25 modifications in m RNA,18 S r RNA,28 S rRNA and small RNA(<200 nt),respectively.Compared to the normal tissues,we revealed a total of 14 RNA modification exhibited significant increase and 2 RNA modifications showed significant decrease in thyroid carcinoma tissues.Our study provided the first comprehensive profile as well as the alteration of modifications in different RNA species in thyroid carcinoma and matched tumor-adjacent normal tissues.The altered pattern RNA modifications may serve as the indicator of thyroid carcinoma.Moreover,this study may promote the in-depth understanding of the regulatory roles of RNA modifications in thyroid carcinoma.
基金Foundation of China for Xiang Cheng(No.81525003)funded this study.
文摘N6-methyladenosine(M6A)is the most common modification in eukaryotic RNAs for the regulation of RNA transcription,processing,splicing,degradation,and translation.RNA modification by M6A is dynamically reversible,involving methylated transferase,demethylase,and methylated reading protein.M6A-mediated gene regulation involves cell differentiation,metastasis,apoptosis,and proliferation.Dysregulation of M6A can lead to various diseases.Cardiovascular disease(CVD)seriously endangers human health and brings great social burden.Seeking effective prevention and treatment strategies for CVD is a challenge to both fundamentalists and clinicians.Substantial evidence has suggested the key role of M6A modification in the development of CVDs.This review summarizes the mechanism of M6A RNA modification and the latest research progress in respect with its role in CVDs,including atherosclerosis,coronary artery disease,myocardial infarction and cardiac remodeling,myocardial ischemia-reperfusion injury,heart failure,hypertension,and aortic aneurysm,and the potential applications of the findings to CVDs,thereby providing new ideas and approaches for the diagnosis and therapy of CVDs.
基金supported by the Mid-Career Researcher Program through the National Research Foundation of Korea funded by the Ministry of Science,ICT,and Future Planning(NRF-2021R1A2C1004187)Republic of Korea+3 种基金the Qing Lan Project of Jiangsu Province(2024)the Natural Science Foundation of Jiangsu Province(grant NoBK20241054)the Program of the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(23KJB550004)the High-Level Innovation and Entrepreneurship Talents Introduction Program of Jiangsu Province of China(JSSCBS20230419).
文摘Epitranscriptomic chemical modifications of RNAs have emerged as potent regulatory mechanisms in the process of plant stress adaptation.Currently,over 170 distinct chemical modifications have been identified in mRNAs,tRNAs,rRNAs,microRNAs(miRNAs),and long noncoding RNAs(lncRNAs).Genetic and molec-ular studies have identified the genes responsible for addition and removal of chemical modifications from RNA molecules,which are known as"writers"and"erasers,"respectively.N^(6)-methyladenosine(m^(6)A)is the most prevalent chemical modification identified in eukaryotic mRNAs.Recent studies have identified m6 A writers and erasers across different plant species,including Arabidopsis(Arabidopsis thaliana),rice(Oryza sativa),cotton(Gossypium hirsutum),and tomato(Solanum lycopersicum).Accumulating discoveries have improved our understanding of the functions of RNA modifications in plant stress responses.This review highlights the latest research on RNA modification,emphasizing the biological and cellular roles of diverse chemical modifications of mRNAs,tRNAs,rRNAs,miRNAs,and lncRNAs in plant responses to environ-mental and hormonal signals.We also propose and discuss critical questions and future challenges for enhancing our understanding of the cellular and mechanistic roles of RNA modifications in plant stress re-sponses.Integrating molecular insights into the regulatory roles of RNA modifications in stress responses with novel genome-and RNA-editing technologies will facilitate the breeding of stress-tolerant crops through precise engineering of RNA modifications.
基金funded by the National Natural Science Foundation of China(32320103010)the National Key Research and Development Program of China(2021YFD1400400)to F.L.+1 种基金the National Natural Science Foundation of China(32302318)to L.G.the National Natural Science Foundation of China(32001868)to H.S.
文摘The chemical modifications of DNA and proteins are powerful mechanisms for regulating molecular and biological functions,influencing a wide array of signaling pathways in eukaryotes.Recent advance-ments in epitranscriptomics have shown that RNA modifications play crucial roles in diverse biological processes.Since their discovery in the 1970s,scientists have sought to decipher,identify,and elucidate the functions of these modifications across biological systems.Over the past decade,mounting evi-dence has demonstrated the importance of RNA modification pathways in plants,prompting significant efforts to decipher their physiological relevance.With the advent of high-resolution mapping tech-niques for RNA modifications and the gradual uncovering of their biological roles,our understanding of this additional layer of regulation is beginning to take shape.In this review,we summarize recent findings on the major RNA modifications identified in plants,with an emphasis on N^(6)-methyladenosine(m^(6)A),the most extensively studied modification.We discuss the functional signifi-cance of the effector components involved in m^(6)A modification and its diverse roles in plant biotic in-teractions,including plant–virus,plant–bacterium,plant–fungus,and plant–insect relationships.Furthermore,we highlight new technological developments driving research progress in this field and outline key challenges that remain to be addressed.
基金support from the National Key R&D Program of China,2023YFF1205600 to C.T.,is acknowledged.
文摘RNA modifications greatly expand the functional diversity of RNA molecules,impacting RNA's stability,folding,and interactions with other biomolecules.These modifications play critical roles in cellular processes and are increasingly linked to disease states.Developments in mass spectrometry(MS),nuclear magnetic resonance(NMR),and chemical probing techniques have provided insights into the mechanisms and functions of RNA modifications.Combining these experimental approaches allows researchers to explore the complexities of RNA modifications and their effects on RNA structure and dynamics.This review highlights recent progresses in the field and examines how the integration of MS,NMR,and complementary techniques is advancing our understanding of RNA modifications and their biological significance.
基金supported by NIH R01 grant(R01DK134549 to X.O.)Yale Liver Center Award NIH P30 DK034989 Morphology Core and the Cellular/Molecular Core(to X.O.)+1 种基金NIH U01 grant(5U01AA026962-02 to W.Z.M.and X.O.)funded by NIH grant(DK P30-034989)。
文摘Non-alcoholic fatty liver disease(NAFLD)has emerged as a prominent global health concern associated with high risk of metabolic syndrome,and has impacted a substantial segment of the population.The disease spectrum ranges from simple fatty liver to non-alcoholic steatohepatitis(NASH),which can progress to cirrhosis and hepatocellular carcinoma(HCC)and is increasingly becoming a prevalent indication for liver transplantation.The existing therapeutic options for NAFLD,NASH,and HCC are limited,underscoring the urgent need for innovative treatment strategies.Insights into gene expression,particularly RNA modifications such as N6methyladenosine(m^(6)A),hold promising avenues for interventions.These modifications play integral roles in RNA metabolism and cellular functions,encompassing the entire NAFLD-NASH-HCC progression.This review will encompass recent insights on diverse RNA modifications,including m^(6)A,pseudouridine(Ψ),N^(1)-methyladenosine(m^(1)A),and 5-methylcytidine(m^(5)C)across various RNA species.It will uncover their significance in crucial aspects such as steatosis,inflammation,fibrosis,and tumorigenesis.Furthermore,prospective research directions and therapeutic implications will be explored,advancing our comprehensive understanding of the intricate interconnected nature of these pathological conditions.
基金Startup Fund from Soochow University,Grant/Award Numbers:Q413900313,Q413900412National Natural Science Foundation of China,Grant/Award Numbers:81773508,82073636,82170480,82173597+1 种基金Project of the Priority Academic Program Development of Jiangsu Higher Education InstitutionsCAMS Innovation Fund for Medical Sciences,Grant/Award Number:(CIFMS)(2021-I2M-1-008)。
文摘Background Genome-wide association studies(GWAS)have identified more than a thousand loci for blood pressure(BP).Functional genes in these loci are cell-type specific.The aim of this study was to elucidate potentially functional genes associated with BP in the aorta through the utilization of RNA modification-associated single-nucleotide polymorphisms(RNAm-SNPs).Methods Utilizing large-scale genetic data of 757,601 individuals from the UK Biobank and International Consortium of Blood Pressure consortium,we identified associations between RNAm-SNPs and BP.The association between RNAm-SNPs,gene expression,and BP were examined.Results A total of 355 RNAm-SNPs related to m6A,m1A,m5C,m7G,and A-to-I modification were associated with BP.The related genes were enriched in the pancreatic secretion pathway and renin secretion pathway.The BP GWAS signals were significantly enriched with m6A-SNPs,highlighting the potential functional relevance of m6A in physiological processes influencing BP.Notably,m6A-SNPs in CYP11B1,PDE3B,HDAC7,ACE,SLC4A7,PDE1A,FRK,MTHFR,NPPA,CACNA1D,and HDAC9 were identified.Differential methylation and differential expression of the BP genes in FTO-overexpression and METTL14-knockdown vascular smooth muscle cells were detected.RNAm-SNPs were associated with ascending and descending aorta diameter and the genes showed differential methylation between aortic dissection(AD)cases and controls.In scRNA-seq study,we identified ARID5A,HLA-DPB1,HLA-DRA,IRF1,LINC01091,MCL1,MLF1,MLXIPL,NAA16,NADK,RERG,SRM,and USP53 as differential expression genes for AD in aortic cells.Conclusion The present study identified RNAm-SNPs in BP loci and elucidated the associations between the RNAm-SNPs,gene expression,and BP.The identified BP-associated genes in aortic cells were associated with AD.
基金supported by National Natural Science Foundation of China(Nos.82125029,82073106,82341016)Science and Technology Projects in Guangzhou(Nos.2023A03J0390,202201020101,202201020124).
文摘RNA modification is an essential component of the epitranscriptome,regulating RNA metabolism and cellular functions.Several types of RNA modifications have been identified to date;they include N^(6)-methyladenosine(m^(6)A),N^(1)-methyladenosine(m1A),5-methylcytosine(m5C),N^(7)-methylguanosine(m^(7)G),N^(6),2′-O-dimethyladenosine(m^(6)Am),N4-acetylcytidine(ac^(4)C),etc.RNA modifications,mediated by regulators including writers,erasers,and readers,are associated with carcinogenesis,tumor microenvironment,metabolic reprogramming,immunosuppression,immunotherapy,chemotherapy,etc.A novel perspective indicates that regulatory subunits and post-translational modifications(PTMs)are involved in the regulation of writer,eraser,and reader functions in mediating RNA modifications,tumorigenesis,and anticancer therapy.In this review,we summarize the advances made in the knowledge of different RNA modifications(especially m^(6)A)and focus on RNA modification regulators with functions modulated by a series of factors in cancer,including regulatory subunits(proteins,noncoding RNA or peptides encoded by long noncoding RNA)and PTMs(acetylation,SUMOylation,lactylation,phosphorylation,etc.).We also delineate the relationship between RNA modification regulator functions and carcinogenesis or cancer progression.Additionally,inhibitors that target RNA modification regulators for anticancer therapy and their synergistic effect combined with immunotherapy or chemotherapy are discussed.
基金supported by grants from the National Key Research and Development Program of China(Nos.2019YFA0111700,2019YFA0802603,2019YFA0801800,and 2021YFA0805703)the National Natural Science Foundation of China(Nos.81970154 and 82270192)CAMS Innovation Fund for Medical Sciences(No.2022-I2M-2-001)
文摘Epitranscriptomics focuses on the RNA-modification-mediated post-transcriptional regulation of gene expression.The past decade has witnessed tremendous progress in our understanding of the landscapes and biological functions of RNA modifications,as prompted by the emergence of potent analytical approaches.The hematopoietic system provides a lifelong supply of blood cells,and gene expression is tightly controlled during the differentiation of hematopoietic stem cells(HSCs).The dysregulation of gene expression during hematopoiesis may lead to severe disorders,including acute myeloid leukemia(AML).Emerging evidence supports the involvement of the mRNA modification system in normal hematopoiesis and AML pathogenesis,which has led to the development of small-molecule inhibitors that target N6-methyladenosine(m^(6)A)modification machinery as treatments.Here,we summarize the latest findings and our most up-to-date information on the roles of m^(6)A and N7-methylguanine in both physiological and pathological conditions in the hematopoietic system.Furthermore,we will discuss the therapeutic potential and limitations of cancer treatments targeting m^(6)A.
基金supported by grants from the National Key Research and Development Program of China(2019YFA0802202)the National Natural Science Foundation of China(U21A20197 and 32270723).
文摘N^(6),2′-O-dimethyladenosine(m^(6)Am)is a prevalent modification frequently found at the 5′cap-adjacent adenosine of messenger RNAs(mRNAs)and small nuclear RNAs(snRNAs)and the internal adenosine of snRNAs.This dynamic and reversible modification is under the regulation of methyltransferases phosphorylated CTD interacting factor 1 and methyltransferase-like protein 4,along with the demethylase fat mass and obesity-associated protein.m^(6)Am RNA modification plays a crucial role in the regulation of pre-mRNA splicing,mRNA stability,and translation,thereby influencing gene expression.In recent years,there has been growing interest in exploring the functions of m^(6)Am and its relevance to human diseases.In this review,we provide a comprehensive overview of the current knowledge concerning m^(6)Am,with a focus on m^(6)Am-modifying enzymes,sequencing approaches for its detection,and its impacts on pre-mRNA splicing,mRNA stability,and translation regulation.Furthermore,we highlight the roles of m^(6)Am in the context of obesity,viral infections,and cancers,unravelling its underlying regulatory mechanisms.
基金funded by the Korea Health Technology R&D Project through the Bio and Medical Technology Development Program of the National Research Foundation,supported by the Ministry of Science and ICT(RS-2023-00210847)and the Ministry of Education(RS-2024-00463331),Republic of Korea.
文摘The discovery of glycosylated RNA molecules,known as glycoRNAs,introduces a novel dimension to cellular biology.This commentary explores the transformative findings surrounding glycoRNAs,emphasizing their unique roles in cancer progression and the therapeutic opportunities they present.GlycoRNAs,through interactions with lectins and immune receptors,may contribute to tumor immune evasion.Moreover,the therapeutic potential of this emerging knowledge includes interventions targeting glycoRNA synthesis and modulation of associated signaling pathways.By highlighting these critical insights,this commentary aims to encourage the development of innovative strategies that could improve cancer prognosis and treatment.
基金supported by the National Basic Research Program of China (Grant Nos. 2016YFC0900302 and 2017YFA0505201)the National Natural Science Foundation of China (Grant No. 21432002)
文摘More than 100 modifications have been found in RNA. Analogous to epigenetic DNA methylation, epitranscriptomic modifications can be written, read, and erased by a complex network of proteins. Apart from Na-methyladenosine （m6A）, N1-methyladenosine （mXA） has been found as a reversible modification in tRNA and mRNA. mlA occurs at positions 9, 14, and 58 of tRNA, with m1A58 being critical for tRNA stability. Other than the hundreds of m1A sites in mRNA and long non-coding RNA transcripts, transcriptome-wide mapping of m1A also identifies 〉 20 m1A sites in mitochondrial genes, m1A in the coding region of mitochondrial transcripts can inhibit the translation of the corresponding proteins. In this review, we summarize the current understanding of mlA in mRNA and tRNA, covering high-throughput sequencing methods developed for m1A methylome, m1A-related enzymes （writers and erasers）, as well as its functions in mRNA and tRNA.
基金supported by the National Key Research and Development Program from the Ministry of Science and Technology of China(Grant No.2016YFC0900300)the Beijing Natural Science Foundation(Grant No.5162012)of China awarded to CY
文摘Ever since the first RNA nucleoside modification was charac- terized in 1957 [1], over 100 distinct chemical modifications have been identified in RNA to date [2]. Most of these modi- fications were characterized in non-coding RNAs （ncRNAs）, including tRNA, rRNA, and small nuclear RNA （snRNA） [3]. Studies in the past few decades have located various mod- ifications in these ncRNAs and revealed their functional roles [3]. For instance, NLmethyladenosine （mlA）, which is typically found at position 58 in the tRNA T-loop of eukaryotes, func- tions to stabilize tRNA tertiary structure [4] and affect transla- tion by regulating the associations between tRNA and polysome [5]. Pseudouridine （tp） in snRNA can fine-tune branch site interactions and affect mRNA splicing [6].
基金supported by the National Key Research and Development Program of China(2020YFA0803400)the National Natural Science Foundation of China(32022040,31971230,31770842)the China Postdoctoral Science Foundation Grants(2020M671253)。
文摘Chemical modifications expand the composition of RNA molecules from four standard nucleosides to over 160 modified nucleosides,which greatly increase the complexity and utility of RNAs.Transfer RNAs(tRNAs)are the most heavily modified cellular RNA molecules and contain the largest variety of modifications.Modification of tRNAs is pivotal for protein synthesis and also precisely regulates the noncanonical functions of tRNAs.Defects in tRNA modifications lead to numerous human diseases.Up to now,more than 100 types of modifications have been found in tRNAs.Intriguingly,some modifications occur widely on all tRNAs,while others only occur on a subgroup of tRNAs or even only a specific tRNA.The modification frequency of each tRNA is approximately 7% to 25%,with 5-20 modification sites present on each tRNA.The occurrence and modulation of tRNA modifications are specifically noticeable as plenty of interplays among different sites and modifications have been discovered.In particular,tRNA modifications are responsive to environmental changes,indicating their dynamic and highly organized nature.In this review,we summarized the known occurrence order,cross-talk,and cooperativity of tRNA modifications.
