N6-methyladenosine(M6A)is the most common modification in eukaryotic RNAs for the regulation of RNA transcription,processing,splicing,degradation,and translation.RNA modification by M6A is dynamically reversible,invol...N6-methyladenosine(M6A)is the most common modification in eukaryotic RNAs for the regulation of RNA transcription,processing,splicing,degradation,and translation.RNA modification by M6A is dynamically reversible,involving methylated transferase,demethylase,and methylated reading protein.M6A-mediated gene regulation involves cell differentiation,metastasis,apoptosis,and proliferation.Dysregulation of M6A can lead to various diseases.Cardiovascular disease(CVD)seriously endangers human health and brings great social burden.Seeking effective prevention and treatment strategies for CVD is a challenge to both fundamentalists and clinicians.Substantial evidence has suggested the key role of M6A modification in the development of CVDs.This review summarizes the mechanism of M6A RNA modification and the latest research progress in respect with its role in CVDs,including atherosclerosis,coronary artery disease,myocardial infarction and cardiac remodeling,myocardial ischemia-reperfusion injury,heart failure,hypertension,and aortic aneurysm,and the potential applications of the findings to CVDs,thereby providing new ideas and approaches for the diagnosis and therapy of CVDs.展开更多
As an essential transcriptional activator,PDX1 plays a crucial role in pancreatic development andβ-cell function.Mutations in the PDX1 gene may lead to type 4 maturityonset diabetes of the young(MODY4)and neonatal di...As an essential transcriptional activator,PDX1 plays a crucial role in pancreatic development andβ-cell function.Mutations in the PDX1 gene may lead to type 4 maturityonset diabetes of the young(MODY4)and neonatal diabetes mellitus.However,the precise mechanisms underlying MODY4 remain elusive due to the paucity of clinical samples and pronounced differences in pancreatic architecture and genomic composition between humans and existing animal models.In this study,three PDX1-mutant cynomolgus macaques were generated using CRISPR/Cas9 technology,all of which succumbed shortly postpartum,exhibiting pancreatic agenesis.Notably,one tri-allelic PDX1-mutant cynomolgus macaque(designated as M4)developed a pancreas,whereas the two monoallelic PDX1-mutant cynomolgus macaques displayed no anatomical evidence of pancreatic formation.RNA sequencing of the M4 pancreas revealed substantial molecular changes in both endocrine and exocrine functions,indicating developmental delay and PDX1haploinsufficiency.A marked change in m6A methylation was identified in the M4 pancreas,confirmed through cultured PDX1-mutantisletorganoids.Notably,overexpression of the m6A modulator METTL3 restored function in heterozygous PDX1-mutant islet organoids.This study highlights a novel role of m6A methylation modification in the progression of MODY4 and provides valuable molecular insights for preclinical research.展开更多
The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms.Methylation of N6 adenosine(m^(6)A)and C5 cytosine(m^(5)C)bases occur on mRNA...The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms.Methylation of N6 adenosine(m^(6)A)and C5 cytosine(m^(5)C)bases occur on mRNAs,tRNA,mt-tRNA,and rRNA species as well as non-coding RNAs.With emerging knowledge of RNA binding proteins that act as writer,reader,and eraser effector proteins,comes a new understanding of physiological processes controlled by these systems.Such processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain,give rise to different forms of disease.In this review,we discuss accumulating evidence that changes in the m^(6)A and m^(5)C methylation systems contribute to neurocognitive disorders.Early studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m^(6)A RNA reader protein.Subsequently,familial mutations within the m^(6)A writer gene METTL5,m^(5)C writer genes NSUN2,NSUN3,NSUN5,and NSUN6,as well as THOC2 and THOC6 that form a protein complex with the m^(5)C reader protein ALYREF,were recognized to cause intellectual development disorders.Similarly,differences in expression of the m^(5)C writer and reader effector proteins,NSUN6,NSUN7,and ALYREF in brain tissue are indicated in individuals with Alzheimer's disease,individuals with a high neuropathological load or have suffered traumatic brain injury.Likewise,an abundance of m^(6)A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases,Alzheimer's disease,and individuals with high cognitive reserve.m^(6)A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson's disease tissue,whilst modified RNAs are misplaced within diseased cells,particularly where synapses are located.In parahippocampal brain tissue,m^(6)A modification is enriched in transcripts associated with psychiatric disorders including conditions with clear cognitive deficits.These findings indicate a diverse set of molecular mechanisms are influenced by RNA methylation systems that can cause neuronal and synaptic dysfunction underlying neurocognitive disorders.Targeting these RNA modification systems brings new prospects for neural regenerative therapies.展开更多
Objective:This study aimed to examine a novel method for prognostic evaluation of patients with oral squamous cell carcinoma(OSCC)based on the expression of heterogeneous nuclear ribonucleoprotein C(HNRNPC),YTH domain...Objective:This study aimed to examine a novel method for prognostic evaluation of patients with oral squamous cell carcinoma(OSCC)based on the expression of heterogeneous nuclear ribonucleoprotein C(HNRNPC),YTH domain-binding protein 2(YTHDF2),and methyltransferase 14(METTL14).Methods:We obtained the RNA sequence and clinical information of OSCC patients from The Cancer Genome Atlas database.An optical method was established by the least absolute shrinkage and selection operator Cox regression algorithm,which was used to calculate the risk score of every sample.In addition,all samples(n=239)were classified into high-risk(n=119)and low-risk(n=120)groups,and the overall survival(OS)time and clinical characteristics were compared between groups.Moreover,bioinformatics analysis was carried out.Gene set enrichment analysis was performed to investigate the signaling pathways of HNRNPC,YTHDF2,and METTL14.Results:The two groups showed significantly different OS time,tumor grades,tumor stages,and pathologic T stages(P<0.05).The receiver operating characteristic analysis identified that our method was effective and it was more accurate than use of age,gender,tumor grade,tumor stage,pathologic T stage,and pathologic N stage in OSCC prognostic prediction.Gene set enrichment analysis revealed that HNRNPC,YTHDF2,and METTL14 were mainly associated with ubiquitin-mediated proteolysis,cell cycle,RNA degradation,and spliceosome signaling pathways.Conclusion:The method based on the expression of HNRNPC,YTHDF2,and METTL14 can predict the prognosis of patients with OSCC independently,and its prognostic value is better than that of clinicopathological characteristic indicators.展开更多
Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more ...Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels.The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated.The diabetic condition facilitates epigenetic changes and influences target gene expression.In this review,we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.展开更多
BACKGROUND Post-translational modifications play key roles in various biological processes.Protein arginine methyltransferases(PRMTs)transfer the methyl group to specific arginine residues.Both PRMT1 and PRMT6 have em...BACKGROUND Post-translational modifications play key roles in various biological processes.Protein arginine methyltransferases(PRMTs)transfer the methyl group to specific arginine residues.Both PRMT1 and PRMT6 have emerges as crucial factors in the development and progression of multiple cancer types.We posit that PRMT1 and PRMT6 might interplay directly or in-directly in multiple ways accounting for shared disease phenotypes.AIM To investigate the mechanism of the interaction between PRMT1 and PRMT6.METHODS Gel electrophoresis autoradiography was performed to test the methyltranferase activity of PRMTs and characterize the kinetics parameters of PRMTs.Liquid chromatography-tandem mass spectrometryanalysis was performed to detect the PRMT6 methylation sites.RESULTS In this study we investigated the interaction between PRMT1 and PRMT6,and PRMT6 was shown to be a novel substrate of PRMT1.We identified specific arginine residues of PRMT6 that are methylated by PRMT1,with R106 being the major methylation site.Combined biochemical and cellular data showed that PRMT1 downregulates the enzymatic activity of PRMT6 in histone H3 methylation.CONCLUSION PRMT6 is methylated by PRMT1 and R106 is a major methylation site induced by PRMT1.PRMT1 methylation suppresses the activity of PRMT6.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
基金Foundation of China for Xiang Cheng(No.81525003)funded this study.
文摘N6-methyladenosine(M6A)is the most common modification in eukaryotic RNAs for the regulation of RNA transcription,processing,splicing,degradation,and translation.RNA modification by M6A is dynamically reversible,involving methylated transferase,demethylase,and methylated reading protein.M6A-mediated gene regulation involves cell differentiation,metastasis,apoptosis,and proliferation.Dysregulation of M6A can lead to various diseases.Cardiovascular disease(CVD)seriously endangers human health and brings great social burden.Seeking effective prevention and treatment strategies for CVD is a challenge to both fundamentalists and clinicians.Substantial evidence has suggested the key role of M6A modification in the development of CVDs.This review summarizes the mechanism of M6A RNA modification and the latest research progress in respect with its role in CVDs,including atherosclerosis,coronary artery disease,myocardial infarction and cardiac remodeling,myocardial ischemia-reperfusion injury,heart failure,hypertension,and aortic aneurysm,and the potential applications of the findings to CVDs,thereby providing new ideas and approaches for the diagnosis and therapy of CVDs.
基金supported by the National Key R&D Program of China(2018YFA0801404,2023YFC3403400)National Natural Science Foundation of China(81941006,32371190,32370878)+2 种基金Guangdong Special Support Program(2019BT02Y276,2024A1515012868)Double First-Class Discipline Promotion Project(2023B10564003)Program for Scientific Research Start-up Funds of Guangdong Ocean University(060302052408)。
文摘As an essential transcriptional activator,PDX1 plays a crucial role in pancreatic development andβ-cell function.Mutations in the PDX1 gene may lead to type 4 maturityonset diabetes of the young(MODY4)and neonatal diabetes mellitus.However,the precise mechanisms underlying MODY4 remain elusive due to the paucity of clinical samples and pronounced differences in pancreatic architecture and genomic composition between humans and existing animal models.In this study,three PDX1-mutant cynomolgus macaques were generated using CRISPR/Cas9 technology,all of which succumbed shortly postpartum,exhibiting pancreatic agenesis.Notably,one tri-allelic PDX1-mutant cynomolgus macaque(designated as M4)developed a pancreas,whereas the two monoallelic PDX1-mutant cynomolgus macaques displayed no anatomical evidence of pancreatic formation.RNA sequencing of the M4 pancreas revealed substantial molecular changes in both endocrine and exocrine functions,indicating developmental delay and PDX1haploinsufficiency.A marked change in m6A methylation was identified in the M4 pancreas,confirmed through cultured PDX1-mutantisletorganoids.Notably,overexpression of the m6A modulator METTL3 restored function in heterozygous PDX1-mutant islet organoids.This study highlights a novel role of m6A methylation modification in the progression of MODY4 and provides valuable molecular insights for preclinical research.
基金funded by Notingham University and the Neuroscience Support Group Charity,UK(to HMK)supported by a CONACYT PhD scholarshipMD?was supported by the Postdoctoral Research Fellowship Program of TUBITAK。
文摘The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms.Methylation of N6 adenosine(m^(6)A)and C5 cytosine(m^(5)C)bases occur on mRNAs,tRNA,mt-tRNA,and rRNA species as well as non-coding RNAs.With emerging knowledge of RNA binding proteins that act as writer,reader,and eraser effector proteins,comes a new understanding of physiological processes controlled by these systems.Such processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain,give rise to different forms of disease.In this review,we discuss accumulating evidence that changes in the m^(6)A and m^(5)C methylation systems contribute to neurocognitive disorders.Early studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m^(6)A RNA reader protein.Subsequently,familial mutations within the m^(6)A writer gene METTL5,m^(5)C writer genes NSUN2,NSUN3,NSUN5,and NSUN6,as well as THOC2 and THOC6 that form a protein complex with the m^(5)C reader protein ALYREF,were recognized to cause intellectual development disorders.Similarly,differences in expression of the m^(5)C writer and reader effector proteins,NSUN6,NSUN7,and ALYREF in brain tissue are indicated in individuals with Alzheimer's disease,individuals with a high neuropathological load or have suffered traumatic brain injury.Likewise,an abundance of m^(6)A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases,Alzheimer's disease,and individuals with high cognitive reserve.m^(6)A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson's disease tissue,whilst modified RNAs are misplaced within diseased cells,particularly where synapses are located.In parahippocampal brain tissue,m^(6)A modification is enriched in transcripts associated with psychiatric disorders including conditions with clear cognitive deficits.These findings indicate a diverse set of molecular mechanisms are influenced by RNA methylation systems that can cause neuronal and synaptic dysfunction underlying neurocognitive disorders.Targeting these RNA modification systems brings new prospects for neural regenerative therapies.
基金supported by the National Natural ScienceFoundation of China(No.81802710).
文摘Objective:This study aimed to examine a novel method for prognostic evaluation of patients with oral squamous cell carcinoma(OSCC)based on the expression of heterogeneous nuclear ribonucleoprotein C(HNRNPC),YTH domain-binding protein 2(YTHDF2),and methyltransferase 14(METTL14).Methods:We obtained the RNA sequence and clinical information of OSCC patients from The Cancer Genome Atlas database.An optical method was established by the least absolute shrinkage and selection operator Cox regression algorithm,which was used to calculate the risk score of every sample.In addition,all samples(n=239)were classified into high-risk(n=119)and low-risk(n=120)groups,and the overall survival(OS)time and clinical characteristics were compared between groups.Moreover,bioinformatics analysis was carried out.Gene set enrichment analysis was performed to investigate the signaling pathways of HNRNPC,YTHDF2,and METTL14.Results:The two groups showed significantly different OS time,tumor grades,tumor stages,and pathologic T stages(P<0.05).The receiver operating characteristic analysis identified that our method was effective and it was more accurate than use of age,gender,tumor grade,tumor stage,pathologic T stage,and pathologic N stage in OSCC prognostic prediction.Gene set enrichment analysis revealed that HNRNPC,YTHDF2,and METTL14 were mainly associated with ubiquitin-mediated proteolysis,cell cycle,RNA degradation,and spliceosome signaling pathways.Conclusion:The method based on the expression of HNRNPC,YTHDF2,and METTL14 can predict the prognosis of patients with OSCC independently,and its prognostic value is better than that of clinicopathological characteristic indicators.
基金supported by the National Natural Science Foundation of China,No.82171062(to JFZ)Aier Eye Hospital Group Scientific Research Fund,No.AF2101D8(to LMG).
文摘Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels.The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated.The diabetic condition facilitates epigenetic changes and influences target gene expression.In this review,we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.
基金Supported by National Institutes of Health,No.5R01GM126154 and No.1R35GM149230。
文摘BACKGROUND Post-translational modifications play key roles in various biological processes.Protein arginine methyltransferases(PRMTs)transfer the methyl group to specific arginine residues.Both PRMT1 and PRMT6 have emerges as crucial factors in the development and progression of multiple cancer types.We posit that PRMT1 and PRMT6 might interplay directly or in-directly in multiple ways accounting for shared disease phenotypes.AIM To investigate the mechanism of the interaction between PRMT1 and PRMT6.METHODS Gel electrophoresis autoradiography was performed to test the methyltranferase activity of PRMTs and characterize the kinetics parameters of PRMTs.Liquid chromatography-tandem mass spectrometryanalysis was performed to detect the PRMT6 methylation sites.RESULTS In this study we investigated the interaction between PRMT1 and PRMT6,and PRMT6 was shown to be a novel substrate of PRMT1.We identified specific arginine residues of PRMT6 that are methylated by PRMT1,with R106 being the major methylation site.Combined biochemical and cellular data showed that PRMT1 downregulates the enzymatic activity of PRMT6 in histone H3 methylation.CONCLUSION PRMT6 is methylated by PRMT1 and R106 is a major methylation site induced by PRMT1.PRMT1 methylation suppresses the activity of PRMT6.
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.
