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
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
N^6-methyladenosine(m^6 A) is an essential RNA modification that regulates key cellular processes, including stem cell renewal,cellular differentiation, and response to DNA damage. Unsurprisingly, aberrant m^6 A methy...N^6-methyladenosine(m^6 A) is an essential RNA modification that regulates key cellular processes, including stem cell renewal,cellular differentiation, and response to DNA damage. Unsurprisingly, aberrant m^6 A methylation has been implicated in the development and maintenance of diverse human cancers. Altered m^6 A levels affect RNA processing, mRNA degradation, and translation of mRNAs into proteins, thereby disrupting gene expression regulation and promoting tumorigenesis. Recent studies have reported that the abnormal expression of m^6 A regulatory enzymes affects m^6 A abundance and consequently dysregulates the expression of tumor suppressor genes and oncogenes, including MYC, SOCS2, ADAM19, and PTEN. In this review, we discuss the specific roles of m^6 A missing space "writers", "erasers", and "readers" in normal physiology and how their altered expression promotes tumorigenesis. We also describe the potential of exploiting the aberrant expression of these enzymes for cancer diagnosis, prognosis, and the development of novel therapies.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
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
RNA N^(6)-methyladenosine modification is the most prevalent internal modification of eukaryotic RNAs and has emerged as a novel field of RNA epigenetics,garnering increased attention.To date,m^(6)A modification has b...RNA N^(6)-methyladenosine modification is the most prevalent internal modification of eukaryotic RNAs and has emerged as a novel field of RNA epigenetics,garnering increased attention.To date,m^(6)A modification has been shown to impact multiple RNA metabolic processes and play a vital role in numerous biological processes.Recent evidence suggests that aberrant m^(6)A modification is a hallmark of cancer,and it plays a critical role in cancer development and progression through multiple mechanisms.Here,we review the biological functions of mRNA m^(6)A modification in various types of cancers,with a particular focus on metabolic reprogramming,programmed cell death and tumor metastasis.Furthermore,we discuss the potential of targetingm^(6)Amodification or its regulatory proteins as a novel approach of cancer therapy and the progress of research on m^(6)A modification in tumor immunity and immunotherapy.Finally,we summarize the development of different m^(6)A detection methods and their advantages and disadvantages.展开更多
N^(6)-methyladenosine(m^(6)A)RNA is the most abundant modification of mRNA,and has been demonstrated in regulating various post-transcriptional processes.Many studies have shown that m^(6)A methylation plays key roles...N^(6)-methyladenosine(m^(6)A)RNA is the most abundant modification of mRNA,and has been demonstrated in regulating various post-transcriptional processes.Many studies have shown that m^(6)A methylation plays key roles in sex determination,neuronal functions,and embryonic development in Drosophila and mammals.Here,we analyzed transcriptome-wide profile of m^(6)A modification in the embryonic development of the destructive agricultural pest Spodoptera frugiperda.We found that the 2 key mRNA m^(6)A methyltransferases SfrMETTL3 and SfrMETTL14 have high homologies with other insects and mammals,suggesting that SfrMETTL3 and SfrMETTL14 may have conserved function among different species.From methylated RNA immunoprecipitation sequencing analysis,we obtained 46869 m^(6)A peaks representing 8587 transcripts in the 2-h embryos after oviposition,and 41389 m^(6)A peaks representing 9230 transcripts in the 24-h embryos.In addition,5995 m^(6)A peaks were differentially expressed including 3752 upregulated and 2243 downregulated peaks.Functional analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes suggested that differentially expressed m^(6)A peak-modified genes were enriched in cell and organ development between the 2-and 24-h embryos.By conjoint analysis of methylated RNA immunoprecipitation-seq and RNA-seq data,we found that RNA m^(6)A methylation may regulate the transcriptional levels of genes related to tissue and organ development from 2-to 24-h embryos.Our study reveals the role of RNA m^(6)A epigenetic regulation in the embryonic development of S.frugiperda,and provides new insights for the embryonic development of insects.展开更多
N^(6)-methyladenosine(m^(6)A)RNA modification is widely perceived as the most abundant and common modification in transcripts.This modification is dynamically regulated by specific m^(6)A“writers”,“erasers”and“re...N^(6)-methyladenosine(m^(6)A)RNA modification is widely perceived as the most abundant and common modification in transcripts.This modification is dynamically regulated by specific m^(6)A“writers”,“erasers”and“readers”and is reportedly involved in the occurrence and development of many diseases.Since m^(6)A RNA modification was discovered in the 1970s,with the progress of relevant research technologies,an increasing number of functions of m^(6)A have been reported,and a preliminary understanding of m^(6)A has been obtained.In this review,we summarize the mechanisms through which m^(6)A RNA modification is regulated from the perspectives of expression,posttranslational modification and protein interaction.In addition,we also summarize how external and internal environmental factors affect m^(6)A RNA modification and its functions in tumors.The mechanisms through which m^(6)A methylases,m^(6)A demethylases and m^(6)A-binding proteins are regulated are complicated and have not been fully elucidated.Therefore,we hope to promote further research in this field by summarizing these mechanisms and look forward to the future application of m^(6)A in tumors.展开更多
N6-Methyladenosine(m^(6)A)is one of the most abundant modifications of eukaryotic mRNA,but its comprehensive biological functionality remains further exploration.In this study,we identified and characterized a new flo...N6-Methyladenosine(m^(6)A)is one of the most abundant modifications of eukaryotic mRNA,but its comprehensive biological functionality remains further exploration.In this study,we identified and characterized a new flowering-promoting gene,EARLY HEADING DATE6(EHD6),in rice.EHD6 encodes an RNA recognition motif(RRM)-containing RNA binding protein that is localized in the non-membranous cytoplasm ribonucleoprotein(RNP)granules and can bind both m^(6)A-modified RNA and unmodified RNA indiscriminately.We found that EHD6 can physically interact with YTH07,a YTH(YT521-B homology)domain-containing m^(6)A reader.We showed that their interaction enhances the binding of an m^(6)A-modified RNA and triggers relocation of a portion of YTH07 from the cytoplasm into RNP granules through phase-separated condensation.Within these condensates,the mRNA of a rice flowering repressor,CONSTANS-like 4(OsCOL4),becomes sequestered,leading to a reduction in its protein abundance and thus accelerated flowering through the Early heading date 1 pathway.Taken together,these results not only shed new light on the molecular mechanism of efficient m^(6)A recognition by the collaboration between an RNA binding protein and YTH family m^(6)A reader,but also uncover the potential for m^(6)A-mediated translation regulation through phaseseparated ribonucleoprotein condensation in rice.展开更多
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Justin Jong-Leong Wong holds a Fellowship from the Cancer Institute of NSW and receives funding from the National Health and Medical Research Council of Australia (Grant No 1128175, 1129901 and 1126306)
文摘N^6-methyladenosine(m^6 A) is an essential RNA modification that regulates key cellular processes, including stem cell renewal,cellular differentiation, and response to DNA damage. Unsurprisingly, aberrant m^6 A methylation has been implicated in the development and maintenance of diverse human cancers. Altered m^6 A levels affect RNA processing, mRNA degradation, and translation of mRNAs into proteins, thereby disrupting gene expression regulation and promoting tumorigenesis. Recent studies have reported that the abnormal expression of m^6 A regulatory enzymes affects m^6 A abundance and consequently dysregulates the expression of tumor suppressor genes and oncogenes, including MYC, SOCS2, ADAM19, and PTEN. In this review, we discuss the specific roles of m^6 A missing space "writers", "erasers", and "readers" in normal physiology and how their altered expression promotes tumorigenesis. We also describe the potential of exploiting the aberrant expression of these enzymes for cancer diagnosis, prognosis, and the development of novel therapies.
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 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supported by the National Key R&D Program of China(2021YFA1302100)Natural Science Foundation of China(82072617 to J.Zheng,82003162 to J.Zhang)+1 种基金Program for Guangdong Introducing Innovative and Entrepreneurial Teams(2017ZT07S096 to D.L.)Sun Yat-sen University Intramural Funds(to D.L.and to J.Zheng).
文摘RNA N^(6)-methyladenosine modification is the most prevalent internal modification of eukaryotic RNAs and has emerged as a novel field of RNA epigenetics,garnering increased attention.To date,m^(6)A modification has been shown to impact multiple RNA metabolic processes and play a vital role in numerous biological processes.Recent evidence suggests that aberrant m^(6)A modification is a hallmark of cancer,and it plays a critical role in cancer development and progression through multiple mechanisms.Here,we review the biological functions of mRNA m^(6)A modification in various types of cancers,with a particular focus on metabolic reprogramming,programmed cell death and tumor metastasis.Furthermore,we discuss the potential of targetingm^(6)Amodification or its regulatory proteins as a novel approach of cancer therapy and the progress of research on m^(6)A modification in tumor immunity and immunotherapy.Finally,we summarize the development of different m^(6)A detection methods and their advantages and disadvantages.
基金supported by China Postdoctoral Science Foundation(2021M691094)the National Natural Science Foundation of China(32070615,81902093)+3 种基金Guangdong Provincial Natural Science Foundation(2021A1515010823 and 2022A1515010569)Guangzhou Science and Technology Project(202002030100)Guangdong Provincial Science and Technology Agricultural Program(KTP20200105)Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme to XYW.We thank the National Center for Protein Sciences at Peking University and Hui Li for assistance with the LC-MS/MS quantification of m^(6)A levels.
文摘N^(6)-methyladenosine(m^(6)A)RNA is the most abundant modification of mRNA,and has been demonstrated in regulating various post-transcriptional processes.Many studies have shown that m^(6)A methylation plays key roles in sex determination,neuronal functions,and embryonic development in Drosophila and mammals.Here,we analyzed transcriptome-wide profile of m^(6)A modification in the embryonic development of the destructive agricultural pest Spodoptera frugiperda.We found that the 2 key mRNA m^(6)A methyltransferases SfrMETTL3 and SfrMETTL14 have high homologies with other insects and mammals,suggesting that SfrMETTL3 and SfrMETTL14 may have conserved function among different species.From methylated RNA immunoprecipitation sequencing analysis,we obtained 46869 m^(6)A peaks representing 8587 transcripts in the 2-h embryos after oviposition,and 41389 m^(6)A peaks representing 9230 transcripts in the 24-h embryos.In addition,5995 m^(6)A peaks were differentially expressed including 3752 upregulated and 2243 downregulated peaks.Functional analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes suggested that differentially expressed m^(6)A peak-modified genes were enriched in cell and organ development between the 2-and 24-h embryos.By conjoint analysis of methylated RNA immunoprecipitation-seq and RNA-seq data,we found that RNA m^(6)A methylation may regulate the transcriptional levels of genes related to tissue and organ development from 2-to 24-h embryos.Our study reveals the role of RNA m^(6)A epigenetic regulation in the embryonic development of S.frugiperda,and provides new insights for the embryonic development of insects.
基金supported by the Research Project of Jiangsu Commission of Health(China)(No.K2019019).
文摘N^(6)-methyladenosine(m^(6)A)RNA modification is widely perceived as the most abundant and common modification in transcripts.This modification is dynamically regulated by specific m^(6)A“writers”,“erasers”and“readers”and is reportedly involved in the occurrence and development of many diseases.Since m^(6)A RNA modification was discovered in the 1970s,with the progress of relevant research technologies,an increasing number of functions of m^(6)A have been reported,and a preliminary understanding of m^(6)A has been obtained.In this review,we summarize the mechanisms through which m^(6)A RNA modification is regulated from the perspectives of expression,posttranslational modification and protein interaction.In addition,we also summarize how external and internal environmental factors affect m^(6)A RNA modification and its functions in tumors.The mechanisms through which m^(6)A methylases,m^(6)A demethylases and m^(6)A-binding proteins are regulated are complicated and have not been fully elucidated.Therefore,we hope to promote further research in this field by summarizing these mechanisms and look forward to the future application of m^(6)A in tumors.
基金supported by the Key Laboratory of Biology,Genetics and Breeding of Japonica Rice in Mid-lower Yangtze River,Ministry of Agriculture and Rural Affairs,China,and the Jiangsu Collaborative Innovation Center for Modern Crop Production,China.Funding for this work was provided by the National Key Research and Development Program of China(2020YFE0202300 and 2021YFD1200504)the National Natural Science Foundation of China(31971910 and 32272115)+1 种基金the National Science Foundation of Jiangsu Province(BK20212010 and BK20230038)the Foundation of Biological Breeding Zhongshan Lab(BM2022008-03,ZSBBL-KY2023-04,and ZSBBL-KY2023-06).
文摘N6-Methyladenosine(m^(6)A)is one of the most abundant modifications of eukaryotic mRNA,but its comprehensive biological functionality remains further exploration.In this study,we identified and characterized a new flowering-promoting gene,EARLY HEADING DATE6(EHD6),in rice.EHD6 encodes an RNA recognition motif(RRM)-containing RNA binding protein that is localized in the non-membranous cytoplasm ribonucleoprotein(RNP)granules and can bind both m^(6)A-modified RNA and unmodified RNA indiscriminately.We found that EHD6 can physically interact with YTH07,a YTH(YT521-B homology)domain-containing m^(6)A reader.We showed that their interaction enhances the binding of an m^(6)A-modified RNA and triggers relocation of a portion of YTH07 from the cytoplasm into RNP granules through phase-separated condensation.Within these condensates,the mRNA of a rice flowering repressor,CONSTANS-like 4(OsCOL4),becomes sequestered,leading to a reduction in its protein abundance and thus accelerated flowering through the Early heading date 1 pathway.Taken together,these results not only shed new light on the molecular mechanism of efficient m^(6)A recognition by the collaboration between an RNA binding protein and YTH family m^(6)A reader,but also uncover the potential for m^(6)A-mediated translation regulation through phaseseparated ribonucleoprotein condensation in rice.
