N6-methyladenosine(m6A)is a reversible epigenetic modification, which is one of the most abundant modifiers in eukaryotic cells and has been commonly reported in messenger RNAs and non-coding RNAs. The processing modi...N6-methyladenosine(m6A)is a reversible epigenetic modification, which is one of the most abundant modifiers in eukaryotic cells and has been commonly reported in messenger RNAs and non-coding RNAs. The processing modification of m6A regulates RNA transcription, processing, splicing, degradation, and translation, and plays an important role in the biological process of tumors. Circular RNA, which lacks the 5' cap structure, has been mistakenly regarded as a "junk sequence" generated by accidental shearing during the transcription process. However, it has been found that circRNAs can be involved in tumor invasion and metastasis through microRNAs, binding proteins, translated peptides, and m6A modifications. In this paper, we reviewed the role of m6A modifications in circRNA regulation and their functions in hepatocellular carcinoma and discussed their potential clinical applications and future development in this field.展开更多
N6-methyladenosine(m^(6)A)RNA modification is a conserved mechanism that regulates the fate of RNA across eukaryotic organisms.Despite its significance,a comprehensive analysis of m^(6)A-related genes in non-model pla...N6-methyladenosine(m^(6)A)RNA modification is a conserved mechanism that regulates the fate of RNA across eukaryotic organisms.Despite its significance,a comprehensive analysis of m^(6)A-related genes in non-model plants,such as kiwifruit,is lacking.Here,we identified 36 m^(6)A-related genes in the kiwifruit genome according to homology and phylogenetic inference.We performed bioinformatics and evolutionary analyses of the writer,eraser,and reader families of m^(6)A modification.Reanalysis of public RNA-seq data collected from samples under various biotic and abiotic stresses indicated that most m^(6)A-related genes were remarkably expressed under different conditions.Through construction of gene co-expression networks,we found significant correlations between several m^(6)A-related genes and transcription factors(TFs)as well as receptor-like genes during the development and ripening of kiwifruit.Furthermore,we performed ATAC-seq assays on diverse kiwifruit tissues to investigate the regulatory mechanisms of m^(6)A-related genes.We identified 10 common open chromatin regions that were present in at least two tissues,and these regions might serve as potential binding sites for MADS protein,C2H2 protein,and other predicted TFs.Our study offers comprehensive insights into the gene family of m^(6)A-related components in kiwifruit,which will lay foundation for exploring mechanisms of post-transcriptional regulation involved in development and adaptation of kiwifruit.展开更多
Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N6-met...Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N6-methyladenosine(m^(6)A) modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes. However, whether m^(6)A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown. We found that expression of methyltransferase 14 protein(METTL14) in the locomotor cortex was high after spinal cord injury and accompanied by elevated m^(6)A levels. Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury. Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction, we found that METTL14 regulated Trib2 expression in an m^(6)A-regulated manner, thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration. Finally, we administered syringin, a stabilizer of METTL14, using molecular docking. Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14. Findings from this study reveal that m^(6)A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.展开更多
N6-methyladenosine(m6A)modification is a reversible process promoted by“writers”,inhibited by“erasers”,and processed by“readers”.During the last decade,increasing emphasis has been placed on the underlying roles...N6-methyladenosine(m6A)modification is a reversible process promoted by“writers”,inhibited by“erasers”,and processed by“readers”.During the last decade,increasing emphasis has been placed on the underlying roles of m6A modification owing to their great importance in biological significance.The abnormal regulation of m6A modification will lead to aberrant cellular behavior and various diseases.Recently,studies have demonstrated that m6A modification is closely associated with the genesis and progression of ocular surface diseases(OSDs).This review focus on the role of m6A modification and research progress in OSDs including fungal keratitis,herpes simplex keratitis,immunerelated keratoconjunctival diseases,pterygium,ocular chemical burns,and Graves’ophthalmopathy,which may provide new insights into and prospective applications for OSDs.展开更多
N6-methyladenosine(m6A)is an important RNA methylation modification involved in regulating diverse biological processes across multiple species.Hence,the identification of m6A modification sites provides valuable insi...N6-methyladenosine(m6A)is an important RNA methylation modification involved in regulating diverse biological processes across multiple species.Hence,the identification of m6A modification sites provides valuable insight into the biological mechanisms of complex diseases at the post-transcriptional level.Although a variety of identification algorithms have been proposed recently,most of them capture the features of m6A modification sites by focusing on the sequential dependencies of nucleotides at different positions in RNA sequences,while ignoring the structural dependencies of nucleotides in their threedimensional structures.To overcome this issue,we propose a cross-species end-to-end deep learning model,namely CR-NSSD,which conduct a cross-domain representation learning process integrating nucleotide structural and sequential dependencies for RNA m6A site identification.Specifically,CR-NSSD first obtains the pre-coded representations of RNA sequences by incorporating the position information into single-nucleotide states with chaos game representation theory.It then constructs a crossdomain reconstruction encoder to learn the sequential and structural dependencies between nucleotides.By minimizing the reconstruction and binary cross-entropy losses,CR-NSSD is trained to complete the task of m6A site identification.Extensive experiments have demonstrated the promising performance of CR-NSSD by comparing it with several state-of-the-art m6A identification algorithms.Moreover,the results of cross-species prediction indicate that the integration of sequential and structural dependencies allows CR-NSSD to capture general features of m6A modification sites among different species,thus improving the accuracy of cross-species identification.展开更多
Growing evidence supports that cancer progression is closely associated with the tumor microenvironment and immune evasion.Importantly,recent studies have revealed the crucial roles of epigenetic regulators in shaping...Growing evidence supports that cancer progression is closely associated with the tumor microenvironment and immune evasion.Importantly,recent studies have revealed the crucial roles of epigenetic regulators in shaping the tumor microenvironment and restoring immune recognition.N^(6)-methyladenosine(m^(6)A)modification,the most prevalent epigenetic modification of mammalian mRNAs,has essential functions in regulating the processing and metabolism of its targeted RNAs,and therefore affects various biological processes including tumorigenesis and progression.Recent studies have demonstrated the critical functions and molecular mechanisms underlying abnormal m^(6)A modification in the regulation of tumor immunity.In this review,we summarize recent research progress in the potential roles of m^(6)A modification in tumor immunoregulation,with a special focus on the anti-tumor processes of immune cells and involvement in immune-associated molecules and pathways.Furthermore,we review current knowledge regarding the close correlation between m6A-related risk signatures and the tumor immune microenvironment landscape,and we discuss the prognostic value and therapeutic efficacy of m^(6)A regulators in a variety of cancer types.展开更多
Background:Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis.In the current study,we determined the relevant players and role of N^(6)-methyladenine(m^(6)A)RNA methylation in cervica...Background:Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis.In the current study,we determined the relevant players and role of N^(6)-methyladenine(m^(6)A)RNA methylation in cervical cancer progression.Methods:The roles of m^(6)A RNA methylation and centromere protein K(CENPK)in cervical cancer were analyzed using bioinformatics analysis.Methylated RNA immunoprecipitation was adopted to detect m^(6)A modification of CENPK mRNA.Human cervical cancer clinical samples,cell lines,and xenografts were used for analyzing gene expression and function.Immunofluorescence staining and the tumorsphere formation,clonogenic,MTT,and EdU assays were performed to determine cell stemness,chemoresistance,migration,invasion,and proliferation in HeLa and SiHa cells,respectively.Western blot analysis,co-immunoprecipitation,chromatin immunoprecipitation,and luciferase reporter,cycloheximide chase,and cell fractionation assays were performed to elucidate the underlying mechanism.Results:Bioinformatics analysis of public cancer datasets revealed firm links between m^(6)A modification patterns and cervical cancer prognosis,especially through ZC3H13-mediated m^(6)A modification of CENPK mRNA.CENPK expression was elevated in cervical cancer,associated with cancer recurrence,and independently predicts poor patient prognosis[hazard ratio=1.413,95%confidence interval=1.078−1.853,P=0.012].Silencing of CENPK prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy in vivo(P<0.001).We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK withβ-catenin,which promotedβ-catenin expression and nuclear translocation,facilitated p53 ubiquitination,and led to activation of Wnt/β-catenin signaling,but suppression of the p53 pathway.This dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness,DNA damage repair pathways necessary for cisplatin/carboplatin resistance,epithelial-mesenchymal transition involved in metastasis,and DNA replication that drove tumor cell proliferation.Conclusions:CENPK was shown to have an oncogenic role in cervical cancer and can thus serve as a prognostic indicator and novel target for cervical cancer treatment.展开更多
Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid peroxidation.It occurs when multiple redoxactive enzymes are ectopically expressed or show abnormal function.Hence,the preci...Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid peroxidation.It occurs when multiple redoxactive enzymes are ectopically expressed or show abnormal function.Hence,the precise regulation of ferroptosis-related molecules is mediated across multiple levels,including transcriptional,posttranscriptional,translational,and epigenetic levels.N^(6)-methyladenosine(m^(6)A)is a highly evolutionarily conserved epigenetic modification in mammals.The m^(6)A modification is commonly linked to tumor proliferation,progression,and therapy resistance because it is involved in RNA metabolic processes.Intriguingly,accumulating evidence suggests that dysregulated ferroptosis caused by the m^(6)A modification drives tumor development.In this review,we summarized the roles of m^(6)A regulators in ferroptosis-mediated malignant tumor progression and outlined the m^(6)A regulatory mechanism involved in ferroptosis pathways.We also analyzed the potential value and application strategies of targeting m^(6)A/ferroptosis pathway in the clinical diagnosis and therapy of tumors.展开更多
RNA N^(6)-methyladenosine(m^(6)A)methylation is the most abundant and conserved RNA modification in eukaryotes.It participates in the regulation of RNA metabolism and various pathophysiological processes.Non-coding RN...RNA N^(6)-methyladenosine(m^(6)A)methylation is the most abundant and conserved RNA modification in eukaryotes.It participates in the regulation of RNA metabolism and various pathophysiological processes.Non-coding RNAs(ncRNAs)are defined as small or long transcripts which do not encode proteins and display numerous biological regulatory functions.Similar to mRNAs,m^(6)A deposition is observed in ncRNAs.Studying RNA m^(6)A modifications on ncRNAs is of great importance specifically to deepen our understanding of their biological roles and clinical implications.In this review,we summarized the recent research findings regarding the mutual regulation between RNA m^(6)A modification and ncRNAs(with a specific focus on microRNAs,long non-coding RNAs,and circular RNAs)and their functions.We also discussed the challenges of m^(6)A-containing ncRNAs and RNA m^(6)A as therapeutic targets in human diseases and their future perspective in translational roles.展开更多
Amyotrophic lateral sclerosis(ALS)is a progressive neurogenerative disorder with uncertain origins.Emerging evidence implicates N6-methyladenosine(m6A)modification in ALS pathogenesis.Methylated RNA immunoprecipitatio...Amyotrophic lateral sclerosis(ALS)is a progressive neurogenerative disorder with uncertain origins.Emerging evidence implicates N6-methyladenosine(m6A)modification in ALS pathogenesis.Methylated RNA immunoprecipitation sequencing(MeRIP-seq)and liquid chromatography–mass spectrometry were utilized for m6A profiling in peripheral immune cells and serum proteome analysis,respectively,in patients with ALS(n=16)and controls(n=6).The single-cell transcriptomic dataset(GSE174332)of primary motor cortex was further analyzed to illuminate the biological implications of differentially methylated genes and cell communication changes.Analysis of peripheral immune cells revealed extensive RNA hypermethylation,highlighting candidate genes with differential m6A modification and expression,including C-X3-C motif chemokine receptor 1(CX3CR1).In RAW264.7 macrophages,disrupted CX3CR1 signaling affected chemotaxis,potentially influencing immune cell migration in ALS.Serum proteome analysis demonstrated the role of dysregulated immune cell migration in ALS.Cell type-specific expression variations of these genes in the central nervous system(CNS),particularly microglia,were observed.Intercellular communication between neurons and glial cells was selectively altered in ALS CNS.This integrated approach underscores m6A dysregulation in immune cells as a potential ALS contributor.展开更多
N6-methyladenosine(m^(6)A)is the most prevalent modification in the eukaryotic transcriptome and has a wide range of functions in coding and noncoding RNAs.It affects the fate of the modified RNA,including its stabili...N6-methyladenosine(m^(6)A)is the most prevalent modification in the eukaryotic transcriptome and has a wide range of functions in coding and noncoding RNAs.It affects the fate of the modified RNA,including its stability,splicing,and translation,and plays an important role in post-transcriptional regulation.Bones play a key role in supporting and pro-tecting muscles and other organs,facilitating the movement of the organism,ensuring blood production,etc.Bone diseases such as osteoarthritis,osteoporosis,and bone tumors are serious public health problems.The processes of bone development and osteogenic differen-tiation require the precise regulation of gene expression through epigenetic mechanisms including histone,DNA,and RNA modifications.As a reversible dynamic epigenetic mark,m^(6)A modifications affect nearly every important biological process,cellular component,and molecular function,including skeletal development and homeostasis.In recent years,studies have shown that m^(6)A modification is involved in osteogenesis and bone-related diseases.In this review,we summarized the proteins involved in RNA m^(6)A modification and the latest progress in elucidating the regulatory role of m^(6)A modification in bone formation and stem cell direc-tional differentiation.We also discussed the pathological roles and potential molecular mech-anisms of m^(6)A modification in bone-related diseases like osteoporosis and osteosarcoma and suggested potential areas for new strategies that could be used to prevent or treat bone de-fects and bone diseases.展开更多
N6-Methyladenosine(m^(6)A)is the most abundant internal chemical modification in eukaryotic mRNA and plays important roles in gene expression regulation,including transcriptional and post-transcriptional regulation.m^...N6-Methyladenosine(m^(6)A)is the most abundant internal chemical modification in eukaryotic mRNA and plays important roles in gene expression regulation,including transcriptional and post-transcriptional regulation.m^(6)A is a reversible modification that is installed,removed,and recognized by methyltransferases(writers),demethylases(erasers),and m^(6)A-binding proteins(readers),respectively.Recently,the breadth of research on m^(6)A in plants has expanded,and the vital roles of m^(6)A in plant development,biotic and abiotic stress responses,and crop trait improvement have been investigated.In this review,we discuss recent developments in research on m^(6)A and highlight the detection methods,distribution,regulatory proteins,and molecular and biological functions of m^(6)A in plants.We also offer some perspectives on future investigations,providing direction for subsequent research on m^(6)A in plants.展开更多
The unicellular green alga Chlamydomonas reinhardtii(hereafter Chlamydomonas)possesses both plant and animal attributes,and it is an ideal model organism for studying fundamental processes such as photosynthesis,sexua...The unicellular green alga Chlamydomonas reinhardtii(hereafter Chlamydomonas)possesses both plant and animal attributes,and it is an ideal model organism for studying fundamental processes such as photosynthesis,sexual reproduction,and life cycle.N^(6)-methyladenosine(m^(6)A)is the most prevalent mRNA modification,and it plays important roles during sexual reproduction in animals and plants.However,the pattern and function of m^(6)A modification during the sexual reproduction of Chlamydomonas remain unknown.Here,we performed transcriptome and methylated RNA immunoprecipitation sequencing(MeRIP-seq)analyses on six samples from different stages during sexual reproduction of the Chlamydomonas life cycle.The results show that m^(6)A modification frequently occurs at the main motif of DRAC(D=G/A/U,R=A/G)in Chlamydomonas mRNAs.Moreover,m^(6)A peaks in Chlamydomonas mRNAs are mainly enriched in the 30 untranslated regions(30 UTRs)and negatively correlated with the abundance of transcripts at each stage.In particular,there is a significant negative correlation between the expression levels and the m^(6)A levels of genes involved in the microtubule-associated pathway,indicating that m^(6)A modification influences the sexual reproduction and the life cycle of Chlamydomonas by regulating microtubule-based movement.In summary,our findings are the first to demonstrate the distribution and the functions of m^(6)A modification in Chlamydomonas mRNAs and provide new evolutionary insights into m^(6)A modification in the process of sexual reproduction in other plant organisms.展开更多
N^(6)-methyladenosine(m^(6)A)methylation is one of the most predominant internal RNA modifications in eukaryotes and has become a hot spot in the field of epigenetics in recent years.Cardiovascular diseases(CVDs)are a...N^(6)-methyladenosine(m^(6)A)methylation is one of the most predominant internal RNA modifications in eukaryotes and has become a hot spot in the field of epigenetics in recent years.Cardiovascular diseases(CVDs)are a leading cause of death globally.Emerging evidence demonstrates that RNA modifications,such as the m^(6)A modification,are associated with the development and progression of many diseases,including CVDs.An increasing body of studies has indicated that programmed cell death(PCD)plays a vital role in CVDs.However,the molecular mechanisms underlying m^(6)A modification and PCD in CVDs remain poorly understood.Herein,elaborating on the highly complex connections between the m^(6)A mechanisms and different PCD signaling pathways and clarifying the exact molecular mechanism of m^(6)A modification mediating PCD have significant meaning in developing new strategies for the prevention and therapy of CVDs.There is great potential for clinical application.展开更多
基金Key Project Research and Development Plan of Hainan Province(No.ZDYF2020134,ZDYF2022SHFZ283)Natural Science Foundation of Hainan Province(No.821QN391)。
文摘N6-methyladenosine(m6A)is a reversible epigenetic modification, which is one of the most abundant modifiers in eukaryotic cells and has been commonly reported in messenger RNAs and non-coding RNAs. The processing modification of m6A regulates RNA transcription, processing, splicing, degradation, and translation, and plays an important role in the biological process of tumors. Circular RNA, which lacks the 5' cap structure, has been mistakenly regarded as a "junk sequence" generated by accidental shearing during the transcription process. However, it has been found that circRNAs can be involved in tumor invasion and metastasis through microRNAs, binding proteins, translated peptides, and m6A modifications. In this paper, we reviewed the role of m6A modifications in circRNA regulation and their functions in hepatocellular carcinoma and discussed their potential clinical applications and future development in this field.
基金the Natural Science Foundation of Zhejiang province(Grant Nos.LQ23C150003,LR23C150001)the National Natural Science Foundation of China(NSFC)(Grant No.32102318)NSFC Excellent Young Scientists Fund.
文摘N6-methyladenosine(m^(6)A)RNA modification is a conserved mechanism that regulates the fate of RNA across eukaryotic organisms.Despite its significance,a comprehensive analysis of m^(6)A-related genes in non-model plants,such as kiwifruit,is lacking.Here,we identified 36 m^(6)A-related genes in the kiwifruit genome according to homology and phylogenetic inference.We performed bioinformatics and evolutionary analyses of the writer,eraser,and reader families of m^(6)A modification.Reanalysis of public RNA-seq data collected from samples under various biotic and abiotic stresses indicated that most m^(6)A-related genes were remarkably expressed under different conditions.Through construction of gene co-expression networks,we found significant correlations between several m^(6)A-related genes and transcription factors(TFs)as well as receptor-like genes during the development and ripening of kiwifruit.Furthermore,we performed ATAC-seq assays on diverse kiwifruit tissues to investigate the regulatory mechanisms of m^(6)A-related genes.We identified 10 common open chromatin regions that were present in at least two tissues,and these regions might serve as potential binding sites for MADS protein,C2H2 protein,and other predicted TFs.Our study offers comprehensive insights into the gene family of m^(6)A-related components in kiwifruit,which will lay foundation for exploring mechanisms of post-transcriptional regulation involved in development and adaptation of kiwifruit.
基金supported by the National Natural Science Foundation of China,Nos.82030071 (to JH),82272495 (to YC)Science and Technology Major Project of Changsha,No.kh2103008 (to JH)Graduate Students’ Independent Innovative Projects of Hunan Province,No.CX20230311 (to YJ)。
文摘Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N6-methyladenosine(m^(6)A) modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes. However, whether m^(6)A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown. We found that expression of methyltransferase 14 protein(METTL14) in the locomotor cortex was high after spinal cord injury and accompanied by elevated m^(6)A levels. Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury. Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction, we found that METTL14 regulated Trib2 expression in an m^(6)A-regulated manner, thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration. Finally, we administered syringin, a stabilizer of METTL14, using molecular docking. Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14. Findings from this study reveal that m^(6)A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.
基金Supported by Project of Shanghai Science and Technology (No.20ZR1443600)。
文摘N6-methyladenosine(m6A)modification is a reversible process promoted by“writers”,inhibited by“erasers”,and processed by“readers”.During the last decade,increasing emphasis has been placed on the underlying roles of m6A modification owing to their great importance in biological significance.The abnormal regulation of m6A modification will lead to aberrant cellular behavior and various diseases.Recently,studies have demonstrated that m6A modification is closely associated with the genesis and progression of ocular surface diseases(OSDs).This review focus on the role of m6A modification and research progress in OSDs including fungal keratitis,herpes simplex keratitis,immunerelated keratoconjunctival diseases,pterygium,ocular chemical burns,and Graves’ophthalmopathy,which may provide new insights into and prospective applications for OSDs.
基金supported in part by the National Natural Science Foundation of China(62373348)the Natural Science Foundation of Xinjiang Uygur Autonomous Region(2021D01D05)+1 种基金the Tianshan Talent Training Program(2023TSYCLJ0021)the Pioneer Hundred Talents Program of Chinese Academy of Sciences.
文摘N6-methyladenosine(m6A)is an important RNA methylation modification involved in regulating diverse biological processes across multiple species.Hence,the identification of m6A modification sites provides valuable insight into the biological mechanisms of complex diseases at the post-transcriptional level.Although a variety of identification algorithms have been proposed recently,most of them capture the features of m6A modification sites by focusing on the sequential dependencies of nucleotides at different positions in RNA sequences,while ignoring the structural dependencies of nucleotides in their threedimensional structures.To overcome this issue,we propose a cross-species end-to-end deep learning model,namely CR-NSSD,which conduct a cross-domain representation learning process integrating nucleotide structural and sequential dependencies for RNA m6A site identification.Specifically,CR-NSSD first obtains the pre-coded representations of RNA sequences by incorporating the position information into single-nucleotide states with chaos game representation theory.It then constructs a crossdomain reconstruction encoder to learn the sequential and structural dependencies between nucleotides.By minimizing the reconstruction and binary cross-entropy losses,CR-NSSD is trained to complete the task of m6A site identification.Extensive experiments have demonstrated the promising performance of CR-NSSD by comparing it with several state-of-the-art m6A identification algorithms.Moreover,the results of cross-species prediction indicate that the integration of sequential and structural dependencies allows CR-NSSD to capture general features of m6A modification sites among different species,thus improving the accuracy of cross-species identification.
基金This research was supported by grants from the National Natural Science Foundation of China(Grant Nos.81922052,81974435,and 81772999)Natural Science Foundation of Guangdong Province(Grant No.2019B151502011)the Guangzhou People’s Livelihood Science and Technology Project(Grant No.201903010006).
文摘Growing evidence supports that cancer progression is closely associated with the tumor microenvironment and immune evasion.Importantly,recent studies have revealed the crucial roles of epigenetic regulators in shaping the tumor microenvironment and restoring immune recognition.N^(6)-methyladenosine(m^(6)A)modification,the most prevalent epigenetic modification of mammalian mRNAs,has essential functions in regulating the processing and metabolism of its targeted RNAs,and therefore affects various biological processes including tumorigenesis and progression.Recent studies have demonstrated the critical functions and molecular mechanisms underlying abnormal m^(6)A modification in the regulation of tumor immunity.In this review,we summarize recent research progress in the potential roles of m^(6)A modification in tumor immunoregulation,with a special focus on the anti-tumor processes of immune cells and involvement in immune-associated molecules and pathways.Furthermore,we review current knowledge regarding the close correlation between m6A-related risk signatures and the tumor immune microenvironment landscape,and we discuss the prognostic value and therapeutic efficacy of m^(6)A regulators in a variety of cancer types.
基金the Joint Funds for the Innovation of Science and Technology Program of Fujian Province,China(2018Y9110)the Natural Science Foundation of Fujian Province,China,(2020J011126)the China Postdoctoral Science Foundation(2021T140468).
文摘Background:Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis.In the current study,we determined the relevant players and role of N^(6)-methyladenine(m^(6)A)RNA methylation in cervical cancer progression.Methods:The roles of m^(6)A RNA methylation and centromere protein K(CENPK)in cervical cancer were analyzed using bioinformatics analysis.Methylated RNA immunoprecipitation was adopted to detect m^(6)A modification of CENPK mRNA.Human cervical cancer clinical samples,cell lines,and xenografts were used for analyzing gene expression and function.Immunofluorescence staining and the tumorsphere formation,clonogenic,MTT,and EdU assays were performed to determine cell stemness,chemoresistance,migration,invasion,and proliferation in HeLa and SiHa cells,respectively.Western blot analysis,co-immunoprecipitation,chromatin immunoprecipitation,and luciferase reporter,cycloheximide chase,and cell fractionation assays were performed to elucidate the underlying mechanism.Results:Bioinformatics analysis of public cancer datasets revealed firm links between m^(6)A modification patterns and cervical cancer prognosis,especially through ZC3H13-mediated m^(6)A modification of CENPK mRNA.CENPK expression was elevated in cervical cancer,associated with cancer recurrence,and independently predicts poor patient prognosis[hazard ratio=1.413,95%confidence interval=1.078−1.853,P=0.012].Silencing of CENPK prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy in vivo(P<0.001).We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK withβ-catenin,which promotedβ-catenin expression and nuclear translocation,facilitated p53 ubiquitination,and led to activation of Wnt/β-catenin signaling,but suppression of the p53 pathway.This dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness,DNA damage repair pathways necessary for cisplatin/carboplatin resistance,epithelial-mesenchymal transition involved in metastasis,and DNA replication that drove tumor cell proliferation.Conclusions:CENPK was shown to have an oncogenic role in cervical cancer and can thus serve as a prognostic indicator and novel target for cervical cancer treatment.
基金supported by the National Natural Science Foundation of China(82172592)the Free Exploration Program of Central South University(2021zzts0934)the program of Introducing Talents of Discipline to Universities(111-2-12)。
文摘Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid peroxidation.It occurs when multiple redoxactive enzymes are ectopically expressed or show abnormal function.Hence,the precise regulation of ferroptosis-related molecules is mediated across multiple levels,including transcriptional,posttranscriptional,translational,and epigenetic levels.N^(6)-methyladenosine(m^(6)A)is a highly evolutionarily conserved epigenetic modification in mammals.The m^(6)A modification is commonly linked to tumor proliferation,progression,and therapy resistance because it is involved in RNA metabolic processes.Intriguingly,accumulating evidence suggests that dysregulated ferroptosis caused by the m^(6)A modification drives tumor development.In this review,we summarized the roles of m^(6)A regulators in ferroptosis-mediated malignant tumor progression and outlined the m^(6)A regulatory mechanism involved in ferroptosis pathways.We also analyzed the potential value and application strategies of targeting m^(6)A/ferroptosis pathway in the clinical diagnosis and therapy of tumors.
基金the National Natural Science Foundation of China(No.82020108002&82225005 to JJ Xiao,82270291 to LJ Wang)the Science and Technology Commission of Shanghai,China(No.23410750100,20DZ2255400&21XD1421300 to JJ Xiao)the Natural Science Foundation of Shanghai,China(No.23ZR1423000 to LJ Wang).
文摘RNA N^(6)-methyladenosine(m^(6)A)methylation is the most abundant and conserved RNA modification in eukaryotes.It participates in the regulation of RNA metabolism and various pathophysiological processes.Non-coding RNAs(ncRNAs)are defined as small or long transcripts which do not encode proteins and display numerous biological regulatory functions.Similar to mRNAs,m^(6)A deposition is observed in ncRNAs.Studying RNA m^(6)A modifications on ncRNAs is of great importance specifically to deepen our understanding of their biological roles and clinical implications.In this review,we summarized the recent research findings regarding the mutual regulation between RNA m^(6)A modification and ncRNAs(with a specific focus on microRNAs,long non-coding RNAs,and circular RNAs)and their functions.We also discussed the challenges of m^(6)A-containing ncRNAs and RNA m^(6)A as therapeutic targets in human diseases and their future perspective in translational roles.
基金supported by the Strategic Priority Research Program(Pilot study)“Biological basis of aging and therapeutic strategies”of the Chinese Academy of Sciences(No.XDB39040000)CAMS Innovation Fund for Medical Sciences(Nos.2021-I2M-1-003 and 2021-I2M-1-034)+2 种基金National High Level Hospital Clinical Research Funding(No.2022-PUMCH-B-017)Beijing Natural Science Foundation(No.7202158)National Natural Science Foundation of China(No.81971293).
文摘Amyotrophic lateral sclerosis(ALS)is a progressive neurogenerative disorder with uncertain origins.Emerging evidence implicates N6-methyladenosine(m6A)modification in ALS pathogenesis.Methylated RNA immunoprecipitation sequencing(MeRIP-seq)and liquid chromatography–mass spectrometry were utilized for m6A profiling in peripheral immune cells and serum proteome analysis,respectively,in patients with ALS(n=16)and controls(n=6).The single-cell transcriptomic dataset(GSE174332)of primary motor cortex was further analyzed to illuminate the biological implications of differentially methylated genes and cell communication changes.Analysis of peripheral immune cells revealed extensive RNA hypermethylation,highlighting candidate genes with differential m6A modification and expression,including C-X3-C motif chemokine receptor 1(CX3CR1).In RAW264.7 macrophages,disrupted CX3CR1 signaling affected chemotaxis,potentially influencing immune cell migration in ALS.Serum proteome analysis demonstrated the role of dysregulated immune cell migration in ALS.Cell type-specific expression variations of these genes in the central nervous system(CNS),particularly microglia,were observed.Intercellular communication between neurons and glial cells was selectively altered in ALS CNS.This integrated approach underscores m6A dysregulation in immune cells as a potential ALS contributor.
基金supported by the National Natural Science Foundation of China(No.81870743,82170934)the Sichuan Science and Technology Program(China)(No.2022YFG0280)。
文摘N6-methyladenosine(m^(6)A)is the most prevalent modification in the eukaryotic transcriptome and has a wide range of functions in coding and noncoding RNAs.It affects the fate of the modified RNA,including its stability,splicing,and translation,and plays an important role in post-transcriptional regulation.Bones play a key role in supporting and pro-tecting muscles and other organs,facilitating the movement of the organism,ensuring blood production,etc.Bone diseases such as osteoarthritis,osteoporosis,and bone tumors are serious public health problems.The processes of bone development and osteogenic differen-tiation require the precise regulation of gene expression through epigenetic mechanisms including histone,DNA,and RNA modifications.As a reversible dynamic epigenetic mark,m^(6)A modifications affect nearly every important biological process,cellular component,and molecular function,including skeletal development and homeostasis.In recent years,studies have shown that m^(6)A modification is involved in osteogenesis and bone-related diseases.In this review,we summarized the proteins involved in RNA m^(6)A modification and the latest progress in elucidating the regulatory role of m^(6)A modification in bone formation and stem cell direc-tional differentiation.We also discussed the pathological roles and potential molecular mech-anisms of m^(6)A modification in bone-related diseases like osteoporosis and osteosarcoma and suggested potential areas for new strategies that could be used to prevent or treat bone de-fects and bone diseases.
基金supported by the National Natural Science Foundation of China(22225704,21820102008,92053109)the National Basic Research Program of China(2019YFA0802201)the Beijing Natural Science Foundation(Z200010).
文摘N6-Methyladenosine(m^(6)A)is the most abundant internal chemical modification in eukaryotic mRNA and plays important roles in gene expression regulation,including transcriptional and post-transcriptional regulation.m^(6)A is a reversible modification that is installed,removed,and recognized by methyltransferases(writers),demethylases(erasers),and m^(6)A-binding proteins(readers),respectively.Recently,the breadth of research on m^(6)A in plants has expanded,and the vital roles of m^(6)A in plant development,biotic and abiotic stress responses,and crop trait improvement have been investigated.In this review,we discuss recent developments in research on m^(6)A and highlight the detection methods,distribution,regulatory proteins,and molecular and biological functions of m^(6)A in plants.We also offer some perspectives on future investigations,providing direction for subsequent research on m^(6)A in plants.
基金supported by the National Key R&D Program of China(Grant Nos.2019YFA0904600,2018YFA0801200,and 2021YFA0910800)the National Natural Science Foundation of China(Grant Nos.31870217 and 91940304).
文摘The unicellular green alga Chlamydomonas reinhardtii(hereafter Chlamydomonas)possesses both plant and animal attributes,and it is an ideal model organism for studying fundamental processes such as photosynthesis,sexual reproduction,and life cycle.N^(6)-methyladenosine(m^(6)A)is the most prevalent mRNA modification,and it plays important roles during sexual reproduction in animals and plants.However,the pattern and function of m^(6)A modification during the sexual reproduction of Chlamydomonas remain unknown.Here,we performed transcriptome and methylated RNA immunoprecipitation sequencing(MeRIP-seq)analyses on six samples from different stages during sexual reproduction of the Chlamydomonas life cycle.The results show that m^(6)A modification frequently occurs at the main motif of DRAC(D=G/A/U,R=A/G)in Chlamydomonas mRNAs.Moreover,m^(6)A peaks in Chlamydomonas mRNAs are mainly enriched in the 30 untranslated regions(30 UTRs)and negatively correlated with the abundance of transcripts at each stage.In particular,there is a significant negative correlation between the expression levels and the m^(6)A levels of genes involved in the microtubule-associated pathway,indicating that m^(6)A modification influences the sexual reproduction and the life cycle of Chlamydomonas by regulating microtubule-based movement.In summary,our findings are the first to demonstrate the distribution and the functions of m^(6)A modification in Chlamydomonas mRNAs and provide new evolutionary insights into m^(6)A modification in the process of sexual reproduction in other plant organisms.
基金the Hunan Provincial Natural Science Foundation of China(No.2022JJ30502,2022JJ30527)the Scientific Research Project of the Hunan Provincial Department of Education(China)(No.20B493)the Health Research Project of the Hunan Provincial Health Commission(China)(No.C202304027603).
文摘N^(6)-methyladenosine(m^(6)A)methylation is one of the most predominant internal RNA modifications in eukaryotes and has become a hot spot in the field of epigenetics in recent years.Cardiovascular diseases(CVDs)are a leading cause of death globally.Emerging evidence demonstrates that RNA modifications,such as the m^(6)A modification,are associated with the development and progression of many diseases,including CVDs.An increasing body of studies has indicated that programmed cell death(PCD)plays a vital role in CVDs.However,the molecular mechanisms underlying m^(6)A modification and PCD in CVDs remain poorly understood.Herein,elaborating on the highly complex connections between the m^(6)A mechanisms and different PCD signaling pathways and clarifying the exact molecular mechanism of m^(6)A modification mediating PCD have significant meaning in developing new strategies for the prevention and therapy of CVDs.There is great potential for clinical application.
