Aberrant RNA modification has been linked to the pathogenesis of various diseases;however,its specific molecular mechanisms in spinal cord injury remain poorly understood.The objective of this study was to explore RNA...Aberrant RNA modification has been linked to the pathogenesis of various diseases;however,its specific molecular mechanisms in spinal cord injury remain poorly understood.The objective of this study was to explore RNA modification-related biomarkers of spinal cord injury.The mRNA expression profiles of mice with spinal cord injury were retrieved from the Gene Expression Omnibus(GEO)database(GSE18179).We identified 185 differentially expressed genes using bioinformatics approaches.Functional enrichment analysis demonstrated aberrant activation or inhibition of common metabolism-related pathways,including sulfur metabolism and steroid biosynthesis,in mice with spinal cord injury.An integrated strategy comprising weighted gene co-expression network analysis,a random forest model,a support vector machine model,and a generalized linear model was employed to identify four genes whose aberrant RNA modification was linked to spinal cord injury:Elovl6,Idi1,Sqle,and Stbd1.We verified the expression levels and diagnostic performance of these four genes in the original training dataset and mouse samples via receiver operating characteristic curve analysis.Quantitative reverse transcription-polymerase chain reaction demonstrated variations in the mRNA levels of the four genes between the Sham and spinal cord injury groups at different time points following injury.We also constructed microRNA-mRNA and transcription factor-mRNA interaction networks using Cytoscape.Additionally,we evaluated the proportions of 22 types of immune cells in the spinal cords of mice using the CIBERSORT tool,revealing significant alterations in the numbers of memory B cells,resting dendritic cells,M0 macrophages,activated mast cells,resting mast cells,and CD8+T cells in spinal cord injury mice compared with Sham controls.Microglia and T cells were identified as key cell types by single-cell sequencing analysis.These findings provide new directions for the development of RNA modification-related therapeutic strategies for spinal cord injury and suggest that Elovl6,Idi1,Sqle,and Stbd1 are potential biomarkers of spinal cord injury.展开更多
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
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
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
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
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
Intestinal macrophages are critical regulators of mucosal immunity,playing essential roles in microbial surveillance,barrier maintenance,and tissue repair.As highly responsive immune cells,they integrate diverse envir...Intestinal macrophages are critical regulators of mucosal immunity,playing essential roles in microbial surveillance,barrier maintenance,and tissue repair.As highly responsive immune cells,they integrate diverse environmental cues to dynamically adapt to their functional states.In recent years,RNA modifications have emerged as a key layer of post-transcriptional regulation,orchestrating macrophage development,polarization,and immunometabolic programming.This review focuses on the role of epitranscriptomic regulation in shaping the plasticity of intestinal macrophages,systematically summarizing how RNA modifications influence their responses to inflammatory stimuli,microbial signals,and intercellular communication.We further highlight the regulatory potential of RNA modifications in gut immune homeostasis and inflammatory diseases,providing a comprehensive framework for understanding RNA-mediated immune regulation and a forward-looking perspective on targeting these pathways in intestinal disorders.展开更多
RNA modifications have emerged as a dynamic and rapidly evolving field in the life sciences,captivating the attention of researchers worldwide due to their profound implications in diverse biological processes and dis...RNA modifications have emerged as a dynamic and rapidly evolving field in the life sciences,captivating the attention of researchers worldwide due to their profound implications in diverse biological processes and disease mechanisms.This special issue aims to compile a comprehensive array of cutting-edge research papers that delve into the multifaceted roles of RNA modifications,offering novel insights and advancing our understanding of this intricate regulatory layer.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
Polycystic ovary syndrome(PCOS)is the most prevalent ovulatory and endocrine disorder affecting reproductive-aged women,yet the absence of a specific,rapid molecular diagnostic marker results in diagnostic delays and ...Polycystic ovary syndrome(PCOS)is the most prevalent ovulatory and endocrine disorder affecting reproductive-aged women,yet the absence of a specific,rapid molecular diagnostic marker results in diagnostic delays and inaccuracies.Given the critical role of RNA modifications in disease pathology,this study utilized a high-throughput RNA modification profiling platform to investigate 15 types of peripheral blood RNA modification patterns in individuals with ovulatory disorders,including PCOS and primary ovarian insufficiency(POI),and control subjects.Our results revealed that distinct modification profiles correspond to specific disease states,with significant shifts in RNA modification inter-correlations observed across conditions.Additionally,specific RNA modifications were associated with clinical features,such as serum levels of testosterone and the follicle number per ovary(FNPO).To optimize diagnostic precision,we evaluated various machine learning models,identifying that combining m6A and m7G modifications in a light gradient boosting machine model(Light GBM)achieves the highest accuracy in distinguishing PCOS,outperforming traditional diagnostic markers.This highlights the potential of RNA modification profiling as a novel,high-accuracy diagnostic tool for PCOS in clinical settings.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
Perfluorooctanoic acid(PFOA)is a highly bioaccumulative environmental endocrine disruptor and a persistent organic pollutant.Epigenetic modifications in DNA and RNA are crucial for regulating gene expression and are i...Perfluorooctanoic acid(PFOA)is a highly bioaccumulative environmental endocrine disruptor and a persistent organic pollutant.Epigenetic modifications in DNA and RNA are crucial for regulating gene expression and are involved in numerous physiological processes.However,research on the effects of PFOA on epigenetic modifications is still limited.In this study,we systematically investigated the alterations in epigenetic modifications in both DNA and RNA from the heart,liver,spleen,lung,kidney,and brain of C57BL/6N mice following exposure to PFOA at doses of 0,0.5,and 5 mg kg^(-1)d^(-1),utilizing liquid chromatography-tandem mass spectrometry(LC-MS/MS).The results indicated that exposure to PFOA inhibited weight gain in mice,and significant changes were observed in the organ coefficients of the liver,spleen,lungs,and heart in the high PFOA exposure group.Modifications in DNA and RNA exhibited tissue specificity.Orthogonal partial least squares discriminant analysis revealed that the control group and the high PFOA exposure group clustered well,suggesting that PFOA exposure significantly impacts epigenetic modifications in DNA and RNA.Specifically,PFOA exposure significantly affected the levels of 5-hydroxymethylcytosine(5hmC)in genomic DNA in the heart,lung,kidney,and liver tissues.For RNA modifications,significant changes were observed,with the levels of 12,13,10,6,12,and 14 modifications in the heart,liver,spleen,lung,kidney,and brain,respectively,altered in response to PFOA exposure.Our study highlights the significance of PFOA exposure in altering DNA and RNA modifications,providing a new perspective on understanding the toxicology of PFOA from an epigenetic standpoint.展开更多
Mitochondria are double-membrane organelles within the cytoplasm,primarily responsible for the efficient production of ATP through oxidative phosphorylation(OXPHOS).These organelles harbor an autonomous genetic system...Mitochondria are double-membrane organelles within the cytoplasm,primarily responsible for the efficient production of ATP through oxidative phosphorylation(OXPHOS).These organelles harbor an autonomous genetic system independent of the nuclear genome,encoded by mitochondrial DNA(mtDNA).Human mitochondria contain a compact 16.6-kilobase circular genome(37 genes,13 protein-coding)that relies on over 1000 nuclear-encoded proteins for its functionality.The mtDNA forms a double-stranded structure where both the sense and antisense strands are transcribed into polycistronic precursors.The heavy(H)strand encodes 12 mRNAs,2 rRNAs,and 14 tRNAs,whereas the light(L)strand produces 1 mRNA and 8 tRNAs.These primary transcripts undergo extensive processing and maturation,including cleavage,RNA modifications,and polyadenylation,yielding functional tRNAs,rRNAs,and mRNAs.Characteristically,most mRNAs and rRNAs are interspersed with tRNA genes,which serve as recognition sites for endonucleases that process the primary transcripts into individual RNA units through site-specific cleavage at tRNA boundaries.展开更多
RNA modifications encompass a series of dynamic chemical changes and editing events on RNA molecules,playing a pivotal role in essential physiological processes such as embryonic development,immune response,and the ma...RNA modifications encompass a series of dynamic chemical changes and editing events on RNA molecules,playing a pivotal role in essential physiological processes such as embryonic development,immune response,and the maintenance of cell homeostasis.By influencing RNA stability,splicing,translation,and intermolecular interactions,RNA modifications serve as crucial mechanisms regulating gene expression at the post-transcriptional level.Dysregulation of the modification machineries or aberrant modification patterns is closely associated with the onset and progression of various diseases,including tumors,metabolic disorders,cardiovascular diseases,and neurological and immune conditions,making them potential biomarkers for disease diagnosis,prognosis,and treatment.In this review,we summarize the molecular mechanisms of major RNA modifications,emphasize their functions in health and disease,and discuss their diagnostic and therapeutic value in pathological contexts.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
N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)...N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)-methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and amyotrophic lateral sclerosis.However,the precise mechanisms by which N^(6)-methyladenosine modification influences these conditions remain unclear.This review summarizes the role of m6A modification and its associated regulators in neurodegeneration,focusing on their involvement in key pathological processes.In Alzheimer’s disease,m6A modification contributes to synaptic dysfunction,mitochondrial damage,and neuronal apoptosis.Evidence from APP/PS1,5xFAD,tau transgenic,and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer’s disease progression through neuroinflammation,circular RNAs dysregulation,and autophagy-related mechanisms.In Parkinson’s disease,altered N^(6)-methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs.In multiple sclerosis and amyotrophic lateral sclerosis,N^(6)-methyladenosine affects immune activation,myelin repair,and the regulation of disease-associated genes such as TDP-43.Beyond N^(6)-methyladenosine,other RNA methylation modifications-such as m1A,m5C,m7G,uracil,and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function,RNA metabolism,and neuronal stress responses.Additionally,N^(6)-methyladenosine exhibits cell type-specific functions:in microglia,it regulates inflammatory activation and phagocytic function;in astrocytes,it modulates metabolic homeostasis and glutamate-associated neurotoxicity;in neurons,it affects synaptic function and neurodegeneration-related gene expression;and in adult neural stem cells,it controls differentiation,neurogenesis,and cognitive plasticity.Recently,several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N^(6)-methyladenosine modification,providing new opportunities for disease intervention,with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy.However,challenges persist in optimizing the specificity and delivery of these therapeutic approaches.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
文摘Aberrant RNA modification has been linked to the pathogenesis of various diseases;however,its specific molecular mechanisms in spinal cord injury remain poorly understood.The objective of this study was to explore RNA modification-related biomarkers of spinal cord injury.The mRNA expression profiles of mice with spinal cord injury were retrieved from the Gene Expression Omnibus(GEO)database(GSE18179).We identified 185 differentially expressed genes using bioinformatics approaches.Functional enrichment analysis demonstrated aberrant activation or inhibition of common metabolism-related pathways,including sulfur metabolism and steroid biosynthesis,in mice with spinal cord injury.An integrated strategy comprising weighted gene co-expression network analysis,a random forest model,a support vector machine model,and a generalized linear model was employed to identify four genes whose aberrant RNA modification was linked to spinal cord injury:Elovl6,Idi1,Sqle,and Stbd1.We verified the expression levels and diagnostic performance of these four genes in the original training dataset and mouse samples via receiver operating characteristic curve analysis.Quantitative reverse transcription-polymerase chain reaction demonstrated variations in the mRNA levels of the four genes between the Sham and spinal cord injury groups at different time points following injury.We also constructed microRNA-mRNA and transcription factor-mRNA interaction networks using Cytoscape.Additionally,we evaluated the proportions of 22 types of immune cells in the spinal cords of mice using the CIBERSORT tool,revealing significant alterations in the numbers of memory B cells,resting dendritic cells,M0 macrophages,activated mast cells,resting mast cells,and CD8+T cells in spinal cord injury mice compared with Sham controls.Microglia and T cells were identified as key cell types by single-cell sequencing analysis.These findings provide new directions for the development of RNA modification-related therapeutic strategies for spinal cord injury and suggest that Elovl6,Idi1,Sqle,and Stbd1 are potential biomarkers of spinal cord injury.
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 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 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 Natural Science Foundation of China(82341017,82030042,82325024,82350112,82461160323,82441048 to Hua-Bing Li)the National Key R&D Program of China(2025YFC3410100 and 2021YFA1100800 to Hua-Bing Li)Shanghai Municipal Health Commission of China(2022XD047 and 2022JC0 to Hua-Bing Li).
文摘Intestinal macrophages are critical regulators of mucosal immunity,playing essential roles in microbial surveillance,barrier maintenance,and tissue repair.As highly responsive immune cells,they integrate diverse environmental cues to dynamically adapt to their functional states.In recent years,RNA modifications have emerged as a key layer of post-transcriptional regulation,orchestrating macrophage development,polarization,and immunometabolic programming.This review focuses on the role of epitranscriptomic regulation in shaping the plasticity of intestinal macrophages,systematically summarizing how RNA modifications influence their responses to inflammatory stimuli,microbial signals,and intercellular communication.We further highlight the regulatory potential of RNA modifications in gut immune homeostasis and inflammatory diseases,providing a comprehensive framework for understanding RNA-mediated immune regulation and a forward-looking perspective on targeting these pathways in intestinal disorders.
文摘RNA modifications have emerged as a dynamic and rapidly evolving field in the life sciences,captivating the attention of researchers worldwide due to their profound implications in diverse biological processes and disease mechanisms.This special issue aims to compile a comprehensive array of cutting-edge research papers that delve into the multifaceted roles of RNA modifications,offering novel insights and advancing our understanding of this intricate regulatory layer.
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supported by the National Natural Science Foundation of China(92357306,82122027,32171110,32370596,82071606,82421004,32588201,32370916)the National Key Research and Development Program of China(2019YFA0802600,2021YFC2700400)+1 种基金Strategic Priority Research Program of the Chinese Academy of Sciences(XDA0460302)Shandong Provincial Key Research and Development Program(2024CXPT087)。
文摘Polycystic ovary syndrome(PCOS)is the most prevalent ovulatory and endocrine disorder affecting reproductive-aged women,yet the absence of a specific,rapid molecular diagnostic marker results in diagnostic delays and inaccuracies.Given the critical role of RNA modifications in disease pathology,this study utilized a high-throughput RNA modification profiling platform to investigate 15 types of peripheral blood RNA modification patterns in individuals with ovulatory disorders,including PCOS and primary ovarian insufficiency(POI),and control subjects.Our results revealed that distinct modification profiles correspond to specific disease states,with significant shifts in RNA modification inter-correlations observed across conditions.Additionally,specific RNA modifications were associated with clinical features,such as serum levels of testosterone and the follicle number per ovary(FNPO).To optimize diagnostic precision,we evaluated various machine learning models,identifying that combining m6A and m7G modifications in a light gradient boosting machine model(Light GBM)achieves the highest accuracy in distinguishing PCOS,outperforming traditional diagnostic markers.This highlights the potential of RNA modification profiling as a novel,high-accuracy diagnostic tool for PCOS in clinical settings.
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supported by the National Key R&D Program of China(Nos.2022YFA0806600,2022YFC3400700)the Fundamental Research Funds for the Central Universities(No.2042024kf1045)+2 种基金the National Natural Science Foundation of China(No.22277093)the Key Research and Development Project of Hubei Province(No.2023BCB094)the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University(No.JCRCGW-2022008)。
文摘Perfluorooctanoic acid(PFOA)is a highly bioaccumulative environmental endocrine disruptor and a persistent organic pollutant.Epigenetic modifications in DNA and RNA are crucial for regulating gene expression and are involved in numerous physiological processes.However,research on the effects of PFOA on epigenetic modifications is still limited.In this study,we systematically investigated the alterations in epigenetic modifications in both DNA and RNA from the heart,liver,spleen,lung,kidney,and brain of C57BL/6N mice following exposure to PFOA at doses of 0,0.5,and 5 mg kg^(-1)d^(-1),utilizing liquid chromatography-tandem mass spectrometry(LC-MS/MS).The results indicated that exposure to PFOA inhibited weight gain in mice,and significant changes were observed in the organ coefficients of the liver,spleen,lungs,and heart in the high PFOA exposure group.Modifications in DNA and RNA exhibited tissue specificity.Orthogonal partial least squares discriminant analysis revealed that the control group and the high PFOA exposure group clustered well,suggesting that PFOA exposure significantly impacts epigenetic modifications in DNA and RNA.Specifically,PFOA exposure significantly affected the levels of 5-hydroxymethylcytosine(5hmC)in genomic DNA in the heart,lung,kidney,and liver tissues.For RNA modifications,significant changes were observed,with the levels of 12,13,10,6,12,and 14 modifications in the heart,liver,spleen,lung,kidney,and brain,respectively,altered in response to PFOA exposure.Our study highlights the significance of PFOA exposure in altering DNA and RNA modifications,providing a new perspective on understanding the toxicology of PFOA from an epigenetic standpoint.
基金supported by the National Key Research and Development Program of China(2022YFC2601800)the National Natural Science Foundation of China(82472761 and 82173833)+6 种基金the Guangdong Basic and Applied Basic Research Foundation(2023B1515040006)the Key-Area Research and Development Program of Guangdong Province(2023B1111020007)the Guangzhou Science and Technology Program(2024A04J6480 and 2025A04J4549)the Guangdong Provincial Key Laboratory of Construction Foundation(2023B1212060022)the Fundamental Research Funds for the Central Universities(Sun Yat-sen University)(24xkjc018)the Basic Scientific Research Fund-Young Faculty Development Program(24qnpy184)the Shenzhen Bay Scholars Program.
文摘Mitochondria are double-membrane organelles within the cytoplasm,primarily responsible for the efficient production of ATP through oxidative phosphorylation(OXPHOS).These organelles harbor an autonomous genetic system independent of the nuclear genome,encoded by mitochondrial DNA(mtDNA).Human mitochondria contain a compact 16.6-kilobase circular genome(37 genes,13 protein-coding)that relies on over 1000 nuclear-encoded proteins for its functionality.The mtDNA forms a double-stranded structure where both the sense and antisense strands are transcribed into polycistronic precursors.The heavy(H)strand encodes 12 mRNAs,2 rRNAs,and 14 tRNAs,whereas the light(L)strand produces 1 mRNA and 8 tRNAs.These primary transcripts undergo extensive processing and maturation,including cleavage,RNA modifications,and polyadenylation,yielding functional tRNAs,rRNAs,and mRNAs.Characteristically,most mRNAs and rRNAs are interspersed with tRNA genes,which serve as recognition sites for endonucleases that process the primary transcripts into individual RNA units through site-specific cleavage at tRNA boundaries.
基金supported by Sichuan Province Science and Technology Support Program(grant No.2022NSFSC0761)Chengdu Medical College Research Foundation(grant No.KYPY22-02)+1 种基金Chengdu Medical College Excellent-talent Program(grant No.2024qnGzn09)Chengdu Medical College Graduate Research Innovation Fund(grant No.YCX2025-01-68).
文摘RNA modifications encompass a series of dynamic chemical changes and editing events on RNA molecules,playing a pivotal role in essential physiological processes such as embryonic development,immune response,and the maintenance of cell homeostasis.By influencing RNA stability,splicing,translation,and intermolecular interactions,RNA modifications serve as crucial mechanisms regulating gene expression at the post-transcriptional level.Dysregulation of the modification machineries or aberrant modification patterns is closely associated with the onset and progression of various diseases,including tumors,metabolic disorders,cardiovascular diseases,and neurological and immune conditions,making them potential biomarkers for disease diagnosis,prognosis,and treatment.In this review,we summarize the molecular mechanisms of major RNA modifications,emphasize their functions in health and disease,and discuss their diagnostic and therapeutic value in pathological contexts.
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 the National Nature Science Foundation of China(General Program),Nos.82271237,82071218(both to JC),and 82230042(to ZY)the Foundation of Key Laboratory of Neurology,Hebei Medical University,Ministry of Education,China,No.2023001(to JC).
文摘N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)-methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and amyotrophic lateral sclerosis.However,the precise mechanisms by which N^(6)-methyladenosine modification influences these conditions remain unclear.This review summarizes the role of m6A modification and its associated regulators in neurodegeneration,focusing on their involvement in key pathological processes.In Alzheimer’s disease,m6A modification contributes to synaptic dysfunction,mitochondrial damage,and neuronal apoptosis.Evidence from APP/PS1,5xFAD,tau transgenic,and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer’s disease progression through neuroinflammation,circular RNAs dysregulation,and autophagy-related mechanisms.In Parkinson’s disease,altered N^(6)-methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs.In multiple sclerosis and amyotrophic lateral sclerosis,N^(6)-methyladenosine affects immune activation,myelin repair,and the regulation of disease-associated genes such as TDP-43.Beyond N^(6)-methyladenosine,other RNA methylation modifications-such as m1A,m5C,m7G,uracil,and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function,RNA metabolism,and neuronal stress responses.Additionally,N^(6)-methyladenosine exhibits cell type-specific functions:in microglia,it regulates inflammatory activation and phagocytic function;in astrocytes,it modulates metabolic homeostasis and glutamate-associated neurotoxicity;in neurons,it affects synaptic function and neurodegeneration-related gene expression;and in adult neural stem cells,it controls differentiation,neurogenesis,and cognitive plasticity.Recently,several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N^(6)-methyladenosine modification,providing new opportunities for disease intervention,with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy.However,challenges persist in optimizing the specificity and delivery of these therapeutic approaches.
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.
