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Dysregulation of rna modification systems in clinical populations with neurocognitive disorders

Neural Regeneration Research 2024年第6期19卷 1256-1261页

作者： Helen M.Knight Merve Demirbugen ?z Adriana PerezGrovas-Saltijeral Division of Cells Organisms and Molecular Genetics School of Life Sciences University of Notingham Department of Pharmaceutical Toxicology Faculty of Pharmacy Ankara University

The study of modified rna known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms. Methylation of N6 adenosine(m6A) and C5 cytosine(m5C) 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 m6A and m5C 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 m6A rna reader protein. Subsequently, familial mutations within the m6A writer gene METTL5, m5C writer genes NSUN2, NSUN3, NSUN5, and NSUN6, as well as THOC2 and THOC6 that form a protein complex with the m5C reader protein ALYREF, were recognized to cause intellectual development disorders. Similarly, differences in expression of the m5C 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 m6A 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. m6A-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, m6A modification is enriched in transcripts associated with psychiatri

关键词： 5-methylcytosine methylation Alzheimer’s disease cognitive diseases epitranscriptomics intellectual disability Lewy body diseases N6 adenosine rna modification

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Unveiling blood pressure-associated genes in aortic cells through integrative analysis of GWAS and rna modification-associated variants

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Chronic Diseases and Translational Medicine 2024年第2期10卷 118-129页

作者： Huan Zhang Yuxi Chen Peng Xu Dan Liu Naqiong Wu Laiyuan Wang Xingbo Mo Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Department of EpidemiologySchool of Public HealthMedical College of Soochow UniversitySuzhouJiangsuChina Cardiometabolic Center Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Key Laboratory of Cardiovascular Epidemiology&Department of Epidemiology State Key Laboratory of Cardiovascular DiseaseFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina MOE Key Laboratory of Geriatric Diseases and Immunology School of Public HealthCenter for Genetic Epidemiology and GenomicsMedical College of Soochow UniversitySuzhouJiangsuChina

Background Genome-wide association studies(GWAS)have identified more than a thousand loci for blood pressure(BP).Functional genes in these loci are cell-type specific.The aim of this study was to elucidate potentially functional genes associated with BP in the aorta through the utilization of rna modification-associated single-nucleotide polymorphisms(rnam-SNPs).Methods Utilizing large-scale genetic data of 757,601 individuals from the UK Biobank and International Consortium of Blood Pressure consortium,we identified associations between rnam-SNPs and BP.The association between rnam-SNPs,gene expression,and BP were examined.Results A total of 355 rnam-SNPs related to m6A,m1A,m5C,m7G,and A-to-I modification were associated with BP.The related genes were enriched in the pancreatic secretion pathway and renin secretion pathway.The BP GWAS signals were significantly enriched with m6A-SNPs,highlighting the potential functional relevance of m6A in physiological processes influencing BP.Notably,m6A-SNPs in CYP11B1,PDE3B,HDAC7,ACE,SLC4A7,PDE1A,FRK,MTHFR,NPPA,CACNA1D,and HDAC9 were identified.Differential methylation and differential expression of the BP genes in FTO-overexpression and METTL14-knockdown vascular smooth muscle cells were detected.rnam-SNPs were associated with ascending and descending aorta diameter and the genes showed differential methylation between aortic dissection(AD)cases and controls.In scrna-seq study,we identified ARID5A,HLA-DPB1,HLA-DRA,IRF1,LINC01091,MCL1,MLF1,MLXIPL,NAA16,NADK,RERG,SRM,and USP53 as differential expression genes for AD in aortic cells.Conclusion The present study identified rnam-SNPs in BP loci and elucidated the associations between the rnam-SNPs,gene expression,and BP.The identified BP-associated genes in aortic cells were associated with AD.

关键词： aortic dissection blood pressure genome-wide association study rna modification single-cell

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Complicated target recognition by archaeal box C/D guide rnas

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Science China(Life Sciences) 2024年第4期67卷 631-644页

作者： Jiayin Wang Songlin Wu Keqiong Ye Key Laboratory of rna Science and Engineering CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China

Box C/D rnas guide the site-specific formation of 2′-O-methylated nucleotides(Nm)of rnas in eukaryotes and archaea.Although C/D rnas have been profiled in several archaea,their targets have not been experimentally determined.Here,we mapped Nm in r rnas,t rnas,and abundant small rnas(s rnas)and profiled C/D rnas in the crenarchaeon Sulfolobus islandicus.The targets of C/D rnas were assigned by analysis of base-pairing interactions,in vitro modification assays,and gene deletion experiments,revealing a complicated landscape of C/D rna-target interactions.C/D rnas widely use dual antisense elements to target adjacent sites in r rnas,enhancing modification at weakly bound sites.Two consecutive sites can be guided with the same antisense element upstream of box D or D′,a phenomenon known as doublespecificity that is exclusive to internal box D′in eukaryotic C/D rnas.Several C/D rnas guide modification at a single non-canonical site.This study reveals the global landscape of rna-guided 2′-O-methylation in an archaeon and unexpected targeting rules employed by C/D rna.

关键词： C/D rna 2′-O-methylation archaea guide rna rna modification

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Graphene as adsorbent for highly efficient extraction of modified nucleosides in urine prior to liquid chromatography-tandem mass spectrometry analysis

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Chinese Chemical Letters 2024年第4期35卷 490-495页

作者： Cheng Guo Xiaoxiao Zhang Xiujuan Hong Yiqiu Hu Lingna Mao Kezhi Jiang Cancer Institute(Key Laboratory of Cancer Prevention and Intervention China National Ministry of Education)The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China Cancer Center Zhejiang UniversityHangzhou 310058China Key Laboratory of Organosilicon Chemistry and Material Technology College of Material Chemistry and Chemical EngineeringHangzhou Normal UniversityHangzhou 311121China Department of General Practice The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China

rna modifications have been involved in numerous biological processes, and aberrations of these modifications are tightly associated with various diseases including cancer. Herein, we developed graphenebased solid-phase extraction and robust ultra performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) combined with stable isotope-dilution for simultaneous enrichment and accurate determination of 17 modified nucleosides in human urine. We found graphene could effectively adsorb various modified nucleosides in human urine samples. With this method, we identified and quantified these modified nucleosides in urine samples collected from lung cancer patients and healthy controls.We revealed that the levels of 12 modified nucleosides were all diminished in urine from lung cancer patients, compared with healthy controls. It is worth noting that we demonstrated, for the first time, the presence of 5,2-O-dimethyluridine(m~5U_m) in human urine. Together, we established a robust analytical method for simultaneous determinations of 17 modified nucleosides in human urine, and our results revealed a close correlation between the concentrations of urinary modified nucleosides and the occurrence of lung cancer, implying the potential applications of these modified nucleosides as noninvasive biomarkers for the early detection of lung cancer. Moreover, this study will stimulate future investigations on the regulatory roles of rna modifications in the initiation and progression of lung cancer.

关键词： Mass spectrometry rna modification Modified nucleosides Graphene Biomarker Urine

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Demethylase-assisted site-specific detection of N^(1)-methyladenosine in rna

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Chinese Chemical Letters 2024年第5期35卷 397-401页

作者： Jun Xiong Ke-Ke Chen Neng-Bin Xie Wei Chen Wen-Xuan Shao Tong-Tong Ji Si-Yu Yu Yu-Qi Feng Bi-Feng Yuan College of Chemistry and Molecular Sciences Research Center of Public HealthRenmin Hospital of Wuhan UniversitySchool of Public HealthWuhan UniversityWuhan 430071China Department of Laboratory Medicine Zhongnan Hospital of Wuhan UniversityWuhan UniversityWuhan 430071China

The dynamic rna modifications have been viewed as new posttranscriptional regulator in modulating gene expression as well as in a broad range of physiological processes.N^(1)-methyladenosine(m^(1)A)is one of the most prevalent modifications existing in multiple types of rnas.In-depth investigation of the functions of m^(1)A requires the site-specific assessment of m^(1)A stoichiometry in rna.Herein,we established a demethylase-assisted method(DA-m^(1)A)for the site-specific detection and quantification of m^(1)A in rna.N^(1)-methyl group in m^(1)A could result in the stalling of reverse transcription at m^(1)A site,thus producing the truncated cDNA.E.coli AlkB is a demethylase that can demethylate m^(1)A to produce adenine in rna,thus generating full-length cDNA from AlkB-treated rna.Evaluation of the produced amounts of full-length cDNA by quantitative real-time PCR can achieve the site-specific detection and quantification of m^(1)A in rna.With the DA-m^(1)A method,we examined and successfully confirmed the previously well-characterized m^(1)A sites in various types of rnas with low false positive rate.In addition,we found that the level of m^(1)A was significantly decreased at the bromodomain containing 2(BRD2)mrna position 1674 and CST telomere replication complex component 1(CTC1)mrna position 5643 in human hepatocellular carcinoma tissues.The results suggest that these two m^(1)A sites in mrna may be involved in liver tumorigenesis.Taken together,the DA-m^(1)A method is simple and enables the rapid,cost-effective,and site-specific detection and quantification of m^(1)A in rna,which provides a valuable tool to decipher the functions of m^(1)A in human diseases.

关键词： N^(1)-methyladenosine rna modification AlkB demethylase rna epigenetics Quantitative real-time PCR Hepatocellular carcinoma

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Sensitive determination of inosine rna modification in single cell by chemical derivatization coupled with mass spectrometry analysis

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中国化学快报:英文版 2023年第10期34卷 98-101页

作者： Wan-Bing Tao Neng-Bin Xie Qing-Yun Cheng Yu-Qi Feng Bi-Feng Yuan College of Chemistry and Molecular Sciences Department of Radiation and Medical OncologyZhongnan Hospital of Wuhan UniversityWuhan UniversityWuhan 430071China School of Public Health Wuhan UniversityWuhan 430071China Research Center of Public Health Renmin Hospital of Wuhan UniversityWuhan 430060China Cancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research Center Zhongnan Hospital of Wuhan UniversityWuhan Research Center for Infectious Diseases and CancerChinese Academy of Medical SciencesWuhan 430071China

Inosine is a vital rna modification across three kingdoms of life.It has been demonstrated that inosine plays important roles in modulation of the fate of rnas.In the current study,we developed a highly sensitive method to determine inosine in a single cell by N-cyclohexyl-N’-β-(4-methylmorpholinium)ethylcarbodiimide p-toluenesulfonate(CMCT)derivatization in combination with mass spectrometry analysis.The results showed that the detection sensitivity of inosine was increased by 556-fold after CMCT derivatization,with the limit of detection(LOD)being 4.5 amol.With the established method,we could detect inosine from 13.0 pg of total rna of HEK293T cells.Meanwhile,inosine in rna from a single cell could also be clearly detected due to the improved detection sensitivity.Moreover,we found the level of inosine in rna of sleep-deprived mice was significantly increased compared to the control mice,indicating that inosine is associated with sleep behavior and might be a potential indicator of sleep disorder.Taken together,the chemical derivatization coupled with mass spectrometry analysis offers a valuable tool in determination of endogenous rna modifications in a single cell,which should benefit the functional study of rna modification in rare clinical samples.

关键词： Inosine rna modification CMCT Derivatization Mass spectrometry Single cell

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Adolescent alcohol exposure changes rna modifications in adult brain by mass spectrometry-based comprehensive profiling analysis

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Chinese Chemical Letters 2024年第1期35卷 461-464页

作者： Ying-Ying Chen Zhu Gui Di Hu Meng-Yuan Chen Jin-Gang He Si-Yu Yu Yu-Qi Feng Jie Wang Bi-Feng Yuan College of Chemistry and Molecular Sciences Research Center of Public HealthRenmin Hospital of Wuhan UniversityWuhan UniversityWuhan 430072China Department of Radiation and Medical Oncology Zhongnan Hospital of Wuhan UniversitySchool of Public HealthWuhan UniversityWuhan 430071China Cancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research Center Zhongnan Hospital of Wuhan UniversityWuhan Research Center for Infectious Diseases and CancerChinese Academy of Medical SciencesWuhan 430071China Key Laboratory of Magnetic Resonance in Biological Systems State Key Laboratory of Magnetic Resonance and Atomic and Molecular PhysicsNational Center for Magnetic Resonance in WuhanWuhan Institute of Physics and MathematicsInnovation Academy for Precision Measurement Science and TechnologyChinese Academy of Sciences-Wuhan National Laboratory for OptoelectronicsWuhan 430071China Phase I Clinical Trial Laboratory Zhongnan Hospital of Wuhan UniversityWuhan 430071China Institute of Neuroscience and Brain Diseases Xiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyang 441000China University of Chinese Academy of Sciences Beijing 101408China

Alcohol consumption is one of the leading causes of death worldwide.Adolescence is a critical period of structural and functional maturation of the brain.Adolescent alcohol use can alter epigenetic modifications.However,little is known on the long-term effects of alcohol consumption during adolescence on rna epigenetic modifications in brain.Herein,we systematically explored the long-term effects of alcohol exposure during adolescence on small rna modifications in adult rat brain tissues by comprehensive liquid chromatography-electrospray ionization-tandem mass spectrometry(LC-ESI-MS/MS)analysis.We totally detected 26 modifications in small rna of brain tissues.Notably,we observed most of these modifications were decreased in brain tissues.These results suggest that alcohol exposure during adolescence may impose a long-lasting impact on rna modifications in brain tissues.This is the first report that alcohol use during adolescence can alter rna modifications in adult brain.Collectively,this study suggests a long-term adverse effects of alcohol consumption on brain from rna epigenetics angle by comprehensive mass spectrometry analysis.

关键词： Mass spectrometry rna modification Adolescence Alcohol exposure Brain

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rna modification by M6A methylation in cardiovascular diseases: Current trends and future directions

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Frigid Zone Medicine 2022年第3期2卷 158-177页

作者： Jinglin Wang Lingfeng Zha Department of Cardiology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China

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.

关键词： rna modification M6A methylation cardiovascular disease epigenetics

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Reversible rna modification N^1-methyladenosine(m^1A) in mrna and trna

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Genomics, Proteomics & Bioinformatics 2018年第3期16卷 155-161页

作者： Chi Zhang Guifang Jia Synthetic and Functional Biomolecules Center Beijing National Laboratory for Molecular Sciences Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education College of Chemistry and Molecular EngineeringPeking University

More than 100 modifications have been found in rna. Analogous to epigenetic DNA methylation, epitranscriptomic modifications can be written, read, and erased by a complex network of proteins. Apart from Na-methyladenosine （m6A）, N1-methyladenosine （mXA） has been found as a reversible modification in trna and mrna. mlA occurs at positions 9, 14, and 58 of trna, with m1A58 being critical for trna stability. Other than the hundreds of m1A sites in mrna and long non-coding rna transcripts, transcriptome-wide mapping of m1A also identifies 〉 20 m1A sites in mitochondrial genes, m1A in the coding region of mitochondrial transcripts can inhibit the translation of the corresponding proteins. In this review, we summarize the current understanding of mlA in mrna and trna, covering high-throughput sequencing methods developed for m1A methylome, m1A-related enzymes （writers and erasers）, as well as its functions in mrna and trna.

关键词： Epitranscriptome rna modification N1-methyladenosine （m1A） m1A writer m1A eraser

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rna m^6A modification and its function in diseases

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Frontiers of Medicine 2018年第4期12卷 481-489页

作者： Jiyu Tong Richard A. Flavell Hua-Bing Li Shanghai Institute of Immunology Department of Microbiology and Immunology Shanghai Jiao Tong University School of Medicine (SJTU- SM) Shanghai 200025 China Department of Immunobiology Yale University School of Medicine New Haven CT 06520 USA Howard Hughes Medical Institute Chevy Chase MD 20815-6789 USA

N^6-methyladenosine （m^6A） is the most common post-transcriptional rna modification throughout the transcriptome, affecting fundamental aspects of rna metabolism, m^6A modification could be installed by m^6A ＂writers＂ composed of core catalytic components （METTL3/METTL14/WTAP） and newly defined regulators and removed by m^6A ＂erasers＂（FTO and ALKBH5）. The function of m^6A is executed by m^6A ＂readers＂ that bind to m^6A directly （YTH domain-containing proteins, eIF3 and IGF2BPs） or indirectly （HNRNPA2B1）. In the past few years, advances in m^6A modulators （＂writers,＂＂erasers,＂ and ＂readers＂） have remarkably renewed our understanding of the function and regulation of m^6A in different cells under normal or disease conditions. However, the mechanism and the regulatory network of m^6A are still largely unknown. Moreover, investigations of the m^6A physiological roles in human diseases are limited. In this review, we summarize the recent advances in m^6A research and highlight the functional relevance and importance of m^6A modification in in vitro cell lines, in physiological contexts, and in cancers.

关键词： rna modification m^6A immunity cancer epigenetics

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