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Salsolinol as an rna m~6A methylation inducer mediates dopaminergic neuronal death by regulating YAP1 and autophagy

Neural Regeneration Research 2025年第3期20卷 887-899页

作者： Jianan Wang Yuanyuan Ran Zihan Li Tianyuan Zhao Fangfang Zhang Juan Wang Zongjian Liu Xuechai Chen Beijing International Science and Technology Cooperation Base for Antiviral Drugs College of Chemistry and LifeBeijing University of TechnologyBeijingChina Department of Rehabilitation Beijing Rehabilitation HospitalCapital Medical UniversityBeijingChina

Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)rna methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).rna sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mrna,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A rna methylation and suggest that Sal may act as an rna methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of rna methylation in the pathogenesis of Parkinson's disease.

关键词： ALKBH5 autophagy FTO Hippo pathway m~6A Parkinson's disease rna methylation salsolinol YAP1 YTHDF2

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Ferroptosis:a critical mechanism of N^(6)-methyladenosine modification involved in carcinogenesis and tumor progression

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Science China(Life Sciences) 2024年第6期67卷 1119-1132页

作者： Qingqing Wei Changning Xue Mengna Li Jianxia Wei Lemei Zheng Shipeng Chen Yumei Duan Hongyu Deng Faqing Tang Wei Xiong Ming Zhou NHC Key Laboratory of Carcinogenesis Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangsha 410013China Cancer Research Institute and School of Basic Medical Sciences Central South UniversityChangsha 410078China The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education Central South UniversityChangsha 410078China Hunan Key Laboratory of Oncotarget Gene Hunan Key Laboratory of Cancer MetabolismHunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangsha 410013China

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.

关键词： ferroptosis m6A modification rna methylation m^(6)A regulator tumor progression

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A neural m^(6)A pathway regulates behavioral aggregation in migratory locusts

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Science China(Life Sciences) 2024年第6期67卷 1242-1254页

作者： Xianliang Huang Qing Li Yanan Xu Ang Li Shanzheng Wang Yusheng Chen Chunrui Zhang Xia Zhang Hailin Wang Cong Lv Baofa Sun Shaoqin Li Le Kang Bing Chen School of Life Science Institutes of Life Science and Green DevelopmentHebei UniversityBaoding 071002China College of Plant Science and Technology Huazhong Agricultural UniversityWuhan 430070China State Key Laboratory of Integrated Management of Pest Insects and Rodents Institute of ZoologyChinese Academy of SciencesBeijing 100101China Institute of Health Sciences Anhui UniversityHefei 230601China Beijing Institute of Genomics Chinese Academy of SciencesBeijing 100101China State Key Laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco-Environmental SciencesChinese Academy of SciencesBeijing100101China

rna N6-methyladenosine(m^(6)A),as the most abundant modification of messenger rna,can modulate insect behaviors,but its specific roles in aggregation behaviors remain unexplored.Here,we conducted a comprehensive molecular and physiological characterization of the individual components of the methyltransferase and demethylase in the migratory locust Locusta migratoria.Our results demonstrated that METTL3,METTL14 and ALKBH5 were dominantly expressed in the brain and exhibited remarkable responses to crowding or isolation.The individual knockdown of methyltransferases(i.e.,METTL3 and METTL14)promoted locust movement and conspecific attraction,whereas ALKBH5 knockdown induced a behavioral shift toward the solitary phase.Furthermore,global transcriptome profiles revealed that m^(6)A modification could regulate the orchestration of gene expression to fine tune the behavioral aggregation of locusts.In summary,our in vivo characterization of the m^(6)A functions in migratory locusts clearly demonstrated the crucial roles of the m^(6)A pathway in effectively modulating aggregation behaviors.

关键词： rna methylation N^(6)-methyladenosine transcriptional orchestration aggregation behavior Locusta migratoria

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Copper-Free Click Chemistry-Mediated Assembly of Single Quantum Dot Nanosensor for Accurately Monitoring Locus-Specific m^(6)A in Cancer Cells

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Chinese Journal of Chemistry 2024年第5期42卷 499-504页

作者： Yue-Ying Li Ning-Ning Zhao Yi-Xuan Geng Qian Han Jian-Ge Qiu Bing-Hua Jiang Zi-Yue Wang Chun-Yang Zhang Translational Medicine Center The First Affiliated Hospital of Zhengzhou UniversityThe Academy of Medical SciencesHenan Institute of Medical and Pharmaceutical Sciences BGI CollegeZhengzhou UniversityZhengzhouHenan450052 China College of Chemistry Chemical Engineering and Materials ScienceShandong Normal UniversityJinanShandong250014 China School of Chemistry and Chemical Engineering Southeast UniversityNanjingJiangsu211189 China

N6-methyladenosine(m^(6)A)plays an important role in embryogenesis,nuclear export,transcription splicing,and protein translation control.Herein,we demonstrate a copper-free click chemistry-mediated assembly of single quantum dot(QD)nanosensor for accurately monitoring locus-specific m^(6)A in cancer cells.The m^(6)A-sensitive endoribonuclease MazF can digest the unmethylated A-rna,and the intact m^(6)A-rna then hybridizes with DNA probes a and b to produce a sandwich hybrid,initiating the click chemistry to generate probe a–b ligation product via first tandem ligation detection reaction(LDR)cycle.Subsequently,DNA probes c and d can hybridize with the probe a–b ligation product to generate the probe c–d ligation product via second LDR cycle.Both LDR cycles can be repeated through denaturation and annealing reaction to generate abundant biotin-/fluorophore-modified probe c–d ligation products that can easily assemble on the QD surface to induce distinct fluorescence resonance energy transfer(FRET)between QD and Cy5.This assay can be homogenously performed without the involvement of copper catalyst,m^(6)A-specific antibody,radioactive labeling,ligase enzyme,enzymatic reverse transcription,and next-generation sequencing.Moreover,it can discriminate even 0.01% m^(6)A level in complex samples and accurately measure cellular m^(6)A-rna expression,providing a promising avenue for clinical diagnostics and biomedical research.

关键词： rna methylation Click chemistry Förster resonance energy transfer Biosensor Cancer

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New insights into developmental biology of Eimeria tenella revealed by comparative analysis of mrna N6-methyladenosine modification between unsporulated oocysts and sporulated oocysts

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Journal of Integrative Agriculture 2024年第1期23卷 239-250页

作者： Qing Liu Bingjin Mu Yijing Meng Linmei Yu Zirui Wang Tao Jia Wenbin Zheng Wenwei Gao Shichen Xie Xingquan Zhu Laboratory of Parasitic Diseases College of Veterinary MedicineShanxi Agricultural UniversityTaigu 030801China Research Center for Parasites&Vectors College of Veterinary MedicineHunan Agricultural UniversityChangsha 410128China

Evidence showed that N6-methyladenosine(m^(6)A)modification plays a pivotal role in influencing rna fate and is strongly associated with cell growth and developmental processes in many species.However,no information regarding m^(6)A modification in Eimeria tenella is currently available.In the present study,we surveyed the transcriptome-wide prevalence of m^(6)A in sporulated oocysts and unsporulated oocysts of E.tenella.Methylated rna immunoprecipitation sequencing(MeRIP-seq)analysis showed that m^(6)A modification was most abundant in the coding sequences,followed by stop codon.There were 3,903 hypermethylated and 3,178 hypomethylated mrnas in sporulated oocysts compared with unsporulated oocysts.Further joint analysis suggested that m^(6)A modification of the majority of genes was positively correlated with mrna expression.The mrna relative expression and m^(6)A level of the selected genes were confirmed by quantitative reverse transcription PCR(RT-qPCR)and MeRIP-qPCR.GO and KEGG analysis indicated that differentially m^(6)A methylated genes(DMMGs)with significant differences in mrna expression were closely related to processes such as regulation of gene expression,epigenetic,microtubule,autophagy-other and TOR signaling.Moreover,a total of 96 DMMGs without significant differences in mrna expression showed significant differences at protein level.GO and pathway enrichment analysis of the 96 genes showed that rna methylation may be involved in cell biosynthesis and metabolism of E.tenella.We firstly present a map of rna m^(6)A modification in E.tenella,which provides significant insights into developmental biology of E.tenella.

关键词： Eimeria tenella m^(6)A rna methylation MeRIP-seq rna-seq proteomic analysis

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Regulation of rna methylation and immune infiltration patterns by m5C regulators in head and neck squamous cell carcinoma

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BIOCELL 2023年第12期47卷 2641-2660页

作者： SHIDA HOU TIANJUN LAN YAOCHENG YANG PEISHENG LIANG XIN LIU JUNJIE WANG ZHIFENG CHEN RONGSHENG ZENG ZIJING HUANG Guanghua School of Stomatology Hospital of StomatologyGuangdong Province Key Laboratory of StomatologySun Yat-sen UniversityGuangzhou510095China Department of Oral and Maxillofacial Surgery Sun Yat-sen Memorial Hospital of Sun Yat-sen UniversityGuangzhou510010China Department of Orthopedics The Second Xiangya HospitalCentral South UniversityChangsha410000China Department of Stomatology Affiliated Hospital of Hangzhou Normal UniversityHangzhou310015China Department of Stomatology Shunde HospitalSouthern Medical University(The First People’s Hospital of Shunde)Foshan528308China Hospital of Stomatology The First Affiliated Hospital of Jinan UniversityGuangzhou510632China Department of Stomatology Nanfang HospitalSouthern Medical UniversityGuangzhou510515China Department of Endodontics Stomatological HospitalSouthern Medical UniversityGuangzhou510280China

5-Methylcytosine(m5C)methylation contributes to the development and progression of various malignant tumors.This study aimed to explore the potential role of m5C methylation regulators(m5CMRs)in head and neck squamous cell carcinoma(HNSCC).Methods:The transcription data of HNSCC samples were obtained from The Cancer Genome Atlas(TCGA)and the Gene Expression Omnibus(GEO)databases.Subsequently,the m5C patterns in HNSCC were evaluated based on 14 m5CMRs.Then,the m5Cscore was developed to quantify m5C patterns by using principal component analysis(PCA)algorithms.Two single-cell rna sequencing datasets and various methods were employed to assess the prognostic value and sensitivity to immunotherapy.Finally,key prognostic m5CMRs were identified using univariate COX regression analysis,and their clinical significance was validated based on the Human Protein Atlas(HPA)database and by using immunohistochemistry.Results:Two distinct m5C clusters were identified.m5C cluster A is characterized by an immune-activated microenvironment and is associated with a favorable prognosis.Notable differences were observed in prognosis,immune infiltration,and immunotherapy response between the high-and low-m5Cscore groups.Patients in the high-m5Cscore group exhibited high TMB,which is correlated with poor prognosis.The m5Cscore of epithelial cells in HNSCC was higher than that in other cells.Key prognostic m5CMRs,including NSUN2,DNMT3B,ALKBH1,and Y-Box Binding Protein 1(YBX1),were associated with poor prognosis.Conclusion:Our research indicates that in head and neck squamous cell carcinoma,the m5C modification profoundly affects the TME’s diversity and complexity,influencing prognosis and the success of immunotherapy.Targeting m5C regulatory elements may be a new method for enhancing the efficacy of immunotherapy in HNSCC.

关键词： Head and neck squamous cell carcinoma rna methylation 5-methylcytosine Immunotherapy

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Research Progress on Epigenetic Mechanism of Sarcopenia

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Journal of Biosciences and Medicines 2024年第4期12卷 149-160页

作者： Lijie Yang Han Lu Yaolei Cha Qing Yang Yuan Zhao Department of Nursing Dali University Dali China

In recent years, sarcopenia, as a progressive muscular atrophy and weakness, has become one of the common diseases in the elderly. Although its cause is not fully understood, a growing body of research suggests that epigenetic mechanisms play an important role in the pathogenesis of sarcopenia. The purpose of this review is to summarize the current research progress in the epigenetics of sarcopenia, focusing on the role of DNA methylation, rna methylation and non-coding rna in the pathogenesis of sarcopenia. While exploring the epigenetic mechanism of sarcopenia, this study will also look into the application prospect of epigenetics in the treatment strategy of sarcopenia, which will provide new ideas and directions for the treatment of sarcopenia.

关键词： Sarcopenia Epigenetics DNA methylation rna methylation Noncoding rna

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5-Methylcytosine rna methylation in Arabidopsis Thaliana

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Molecular Plant 2017年第11期10卷 1387-1399页

作者： Xuean Cui Zhe Liang Lisha Shen Qian Zhang Shengjie Bao Yuke Geng Bin Zhang Vonny Leo Leah A. Vardy Tiegang Lu Xiaofeng Gu Hao Yu Biotechnology Research Institute Chinese Academy of Agricultural Sciences Beijing 100081 China Department of Biological Sciences and Temasek Life Sciences Laboratory National University of Singapore 117543 Singapore Singapore Institute of Medical Biology Agency for Science Technology and Research (A^+STAR) 8A Biomedical Grove #06-06 Immunos 138648 Singapore Singapore

5-Methylcytosine （m^5C） is a well-characterized DNA modification, and is also predominantly reported in abundant non-coding rnas in both prokaryotes and eukaryotes. However, the distribution and biological functions of m^5C in plant mrnas remain largely unknown. Here, we report transcriptome-wide profiling of rna m^5C in Arabidopsis thaliana by applying m^5C rna immunoprecipitation followed by a deep- sequencing approach （m^5C-RIP-seq）. LC-MS/MS and dot blot analyses reveal a dynamic pattern of m^5C mrna modification in various tissues and at different developmental stages, m^5C-RIP-seq analysis identified 6045 m^5C peaks in 4465 expressed genes in young seedlings. We found that m^5C is enriched in coding sequences with two peaks located immediately after start codons and before stop codons, and is associated with mrnas with low translation activity. We further demonstrated that an rna （cytosine-5）-methyl- transferase, trna-specific methyltransferase 4B （TRM4B）, exhibits m^5C rna methyltransferase activity. Mutations in TRM4B display defects in root development and decreased m^5C peaks. TRM4B affects the transcript levels of the genes involved in root development, which is positively correlated with their mrna stability and m^5C levels. Our results suggest that m^5C in mrna is a new epitranscriptome marker inArabidopsis, and that regulation of this modification is an integral part of gene regulatory networks underlying plant development.

关键词： 5-methylcytosine （m^5C） Arabidopsis rna methylation TRM4B root development

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N4-methylcytidine ribosomal rna methylation in chloroplasts is crucial for chloroplast function,development,and abscisic acid response in Arabidopsis

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Journal of Integrative Plant Biology 2021年第3期63卷 570-582页

作者： Le Nguyen Tieu Ngoc Su Jung Park Trinh Thi Huong Kwang Ho Lee Hunseung Kang Department of Applied Biology College of Agriculture and Life SciencesChonnam National UniversityGwangju 61186Republic of Korea Faculty of Forestry Agriculture Tay Nguyen UniversityBuonMaThuotDakLak63000Vietnam Center for Research Facilities Chonnam National UniversityGwangju 61186Republic of Korea

Although the essential role of messenger rna methylation in the nucleus is increasingly understood,the nature of ribosomal rna(rrna)methyltransferases and the role of rrna methylation in chloroplasts remain largely unknown.A recent study revealed that CMAL(for Chloroplast mraW-Like)is a chloroplast-localized rrna methyltransferase that is responsible for N4-methylcytidine(m^(4)C)in 16S chloroplast rrna in Arabidopsis thaliana.In this study,we further examined the role of CMAL in chloroplast biogenesis and function,development,and hormone response.The cmal mutant showed reduced chlorophyll biosynthesis,photosynthetic activity,and growth-defect phenotypes,including severely stunted stems,fewer siliques,and lower seed yield.The cmal mutant was hypersensitive to chloroplast translation inhibitors,such as lincomycin and erythromycin,indicating that the m^(4)C methylation defect in the 16S rrna leads to a reduced translational activity in chloroplasts.Importantly,the stunted stem of the cmal mutant was partially rescued by exogenous gibberellic acid or auxin.The cmal mutant grew poorer than wild type,whereas the CMAL-overexpressing transgenic Arabidopsis plants grew better than wild type in the presence of abscisic acid.Altogether,these results indicate that CMAL is an indispensable rrna methyltransferase in chloroplasts and is crucial for chloroplast biogenesis and function,photosynthesis,and hormone response during plant growth and development.

关键词： abiotic stress Arabidopsis chloroplast CMAL rna methylation rrna methylation

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Integrating transcriptomes and somatic mutations to identify rna methylation regulators as a prognostic marker in hepatocellular carcinoma

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Hepatobiliary & Pancreatic Diseases International 2021年第1期20卷 34-45页

作者： Yue Yan Yun-Hai Luo Dao-Feng Zheng Tong Mu Zhong-Jun Wu Department of Hepatobiliary Surgery The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China

Background:rna methylation modifying plays an important role in the occurrence and progression of a range of human cancers including hepatocellular carcinoma(HCC),which is characterized by a mass of genetic and epigenetic alterations.However,the treatment targeting these alterations is limited.Methods:We used comprehensive bioinformatics analysis to analyze the correlation between cancerassociated rna methylation regulators and HCC malignant features in network datasets.Results:We identified two HCC subgroups(cluster 1 and 2),which had clearly distinct clinicopathological,biofunctional and prognostic characteristics,by consensus clustering.The cluster 2 subgroup correlated with malignancy of the primary tumor,higher tumor stage,higher histopathological grade and higher frequency of TP53 mutation,as well as with shorter survival when compared with cluster 1.Gene enrichment indicated that the cluster 2 correlated to the tumor malignancy signaling and biological processes.Based on these findings,an 11-gene risk signature was built,which not only was an independent prognostic marker but also had an excellent power to predict the tumor features.Conclusions:Our study indicated that rna methylation regulators are vital for HCC malignant progression and provide an important evidence for rna methylation,methylation regulators are actionable targets for anticancer drug discovery.

关键词： rna methylation Hepatocellular carcinoma Prognostic marker Epigenetics

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