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N^6 -methyl-adenosine (m^6 A) in RNA: An Old Modification with A Novel Epigenetic Function

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Genomics, Proteomics & Bioinformatics 2013年第1期11卷 8-17页

作者： Yamei Niu Xu Zhao Yong-Sheng Wu Ming-Ming Li Xiu-Jie Wang Yun-Gui Yang Disease Genomics and Individualized Medicine Laboratory Beijing Institute of GenomicsChinese Academy of Sciences University of Chinese Academy of Sciences Institute of Genetics and Developmental Biology Chinese Academy of Sciences

N6-methyl-adenosine （m6A） is one of the most common and abundant modifications on RNA molecules present in eukaryotes. However, the biological significance of m6A methylation remains largely unknown. Several independent lines of evidence suggest that the dynamic regulation ofm6A may have a profound impact on gene expression regulation. The m6A modification is catalyzed by an unidentified methyltransferase complex containing at least one subunit methyltransferase like 3 （METTL3）. m6A modification on messenger RNAs （mRNAs） mainly occurs in the exonic regions and 3＇-untranslated region （3＇-UTR） as revealed by high-throughput m6A-seq. One significant advance in m6A research is the recent discovery of the first two m6A RNA demethylases fat mass and obesity- associated （FTO） gene and ALKBH5, which catalyze m6A demethylation in an cx-ketoglutarate （a-KG）- and FeZ ＋ -dependent manner. Recent studies in model organisms demonstrate that METTL3, FTO and ALKBH5 play important roles in many biological processes, ranging from devel- opment and metabolism to fertility. Moreover, perturbation of activities of these enzymes leads to the disturbed expression of thousands of genes at the cellular level, implicating a regulatory role ofm6A in RNA metabolism. Given the vital roles of DNA and histone methylations in epigenetic regulation of basic life processes in mammals, the dynamic and reversible chemical m6A modification on RNA may also serve as a novel epigenetic marker of profound biological significances.

关键词： N6-methyl-adenosineMETTL3 FTO ALKBH5 RNA metabolism

m^(6)A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration

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Signal Transduction and Targeted Therapy 2022年第7期7卷 2608-2622页

作者： Yang Liu Renjie Song Lu Zhao Zhike Lu Yini Li Xinyi Zhan Fengjiao Lu Jiang Yang Yamei Niu Xuetao Cao Department of Immunology Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical Sciences100005 BeijingChina Frontier Research Center for Cell Response Institute of ImmunologyCollege of Life SciencesNankai University300071 TianjinChina School of Life Sciences Westlake University310024 HangzhouChina Department of Pathology Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical Sciences100005 BeijingChina.

Neutrophil migration into the site of infection is necessary for antibacterial innate defense,whereas impaired neutrophil migration may result in excessive inflammation and even sepsis.The neutrophil migration directed by extracellular signals such as chemokines has been extensively studied,yet the intrinsic mechanism for determining neutrophil ability to migrate needs further investigation.N6-methyladenosine(m^(6)A)RNA modification is important in immunity and inflammation,and our preliminary data indicate downregulation of RNA m^(6)A demethylase alkB homolog 5(ALKBH5)in neutrophils during bacterial infection.Whether m^(6)A modification and ALKBH5 might intrinsically modulate neutrophil innate response remain unknown.Here we report that ALKBH5 is required for antibacterial innate defense by enhancing intrinsic ability of neutrophil migration.We found that deficiency of ALKBH5 increased mortality of mice with polymicrobial sepsis induced by cecal ligation and puncture(CLP),and Alkbh5-deficient CLP mice exhibited higher bacterial burden and massive proinflammatory cytokine production in the peritoneal cavity and blood because of less neutrophil migration.Alkbh5-deficient neutrophils had lower CXCR2 expression,thus exhibiting impaired migration toward chemokine CXCL2.Mechanistically,ALKBH5-mediated m^(6)A demethylation empowered neutrophils with high migration capability through altering the RNA decay,consequently regulating protein expression of its targets,neutrophil migration-related molecules,including increased expression of neutrophil migration-promoting CXCR2 and NLRP12,but decreased expression of neutrophil migration-suppressive PTGER4,TNC,and WNK1.Our findings reveal a previously unknown role of ALKBH5 in imprinting migrationpromoting transcriptome signatures in neutrophils and intrinsically promoting neutrophil migration for antibacterial defense,highlighting the potential application of targeting neutrophil m^(6)A modification in controlling bacterial infections.

关键词： neutrophil impaired immunity

HIV encephalopathy is contributed by macrophages and microglia

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Science China(Life Sciences) 2024年第4期67卷 836-838页

作者： Si-Meng Liu Man Li Chunhui Ma Chunying Liu An Lv Qing Li Yamei Niu Peng Wang Bo Huang Wei-Min Tong Department of Pathology China Medical UniversityShenyang 110122China Department of Pathology Institute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeNeuroscience CenterChinese Academy of Medical SciencesBeijing 100005China Department of Pathology Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China Molecular Pathology Research Center Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Center For Experimental Animal Research Institute of Basic Medical SciencesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100005China Department of Immunology and National Key Laboratory of Medical Molecular Biology Institute of Basic Medical SciencesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100010China Department of Biochemistry and Molecular Biology Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Dear Editor,Acquired immunodeficiency syndrome(AIDS),characterized by a significant decrease in the number of CD4^(+)T cells,causes a defective T cell immune response,which subsequently leads to various conditional pathogenic infections and tumors(Calmy et al.,2018;Seligmann et al.,1987).Neurological disorders have been reported in 70%–80%of patients with AIDS(Saylor et al.,2016)。

关键词： encephalopathy immunodeficiency

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艾滋病脑病的病理及发病机制

中华病理学杂志 2022年第11期51卷 1186-1188页

作者：刘思梦牛亚梅佟伟民中国医学科学院基础医学研究所暨北京协和医学院基础学院病理学系北京100005 中国医科大学基础医学院病理学教研室沈阳110122

艾滋病,即获得性免疫缺陷综合征(acquired immunodeficiency syndrome,AIDS),其主要特征为CD4阳性淋巴细胞数量显著减少,引起机体免疫功能不足,继而引发各种条件致病菌感染以及肿瘤等疾病,最终导致患者死亡。其中,艾滋病患者常伴发中枢... 详细信息

艾滋病,即获得性免疫缺陷综合征(acquired immunodeficiency syndrome,AIDS),其主要特征为CD4阳性淋巴细胞数量显著减少,引起机体免疫功能不足,继而引发各种条件致病菌感染以及肿瘤等疾病,最终导致患者死亡。其中,艾滋病患者常伴发中枢神经系统感染,即艾滋病脑病,其典型的病理特征是血管周围有大量炎性细胞浸润,其发病机制可能是人类免疫缺陷病毒本身及其分泌的蛋白引起神经系统炎症反应并导致神经元继发性损伤,但艾滋病脑病确切的发病机制仍有待进一步深入探究。

关键词：中枢神经系统感染艾滋病脑病致病菌感染人类免疫缺陷病毒炎性细胞浸润 immunodeficiency 艾滋病患者机体免疫功能

Genome-wide 5-Hydroxymethylcytosine Profiling Analysis Identifies MAP7D1 as A Novel Regulator of Lymph Node Metastasis in Breast Cancer

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Genomics, Proteomics & Bioinformatics 2021年第1期19卷 64-79页

作者： Shuang-Ling Wu Xiaoyi Zhang Mengqi Chang Changcai Huang Jun Qian Qing Li Fang Yuan Lihong Sun Xinmiao Yu Xinmiao Cui Jiayi Jiang Mengyao Cui Ye Liu Huan-Wen Wu Zhi-Yong Liang Xiaoyue Wang Yamei Niu Wei-Min Tong Feng Jin Department of Surgical Oncology and Breast Surgery the First Affiliated Hospital of China Medical UniversityShenyang 110000China Department of Pathology Institute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeMolecular Pathology Research CenterChinese Academy of Medical SciencesBeijing 100005China State Key Laboratory of Medical Molecular Biology Department of Biochemistry and Center for BioinformaticsInstitute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing 100005China Beijing National Laboratory for Molecular Sciences(BNLMS) MOE Key Laboratory of Bioorganic Chemistry and Molecular EngineeringCollege of ChemistryPeking UniversityBeijing 100871China Center for Experimental Animal Research Institute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing 100005China Department of Pathology Peking Union Medical College HospitalChinese Academy of Medical SciencesPeking Union Medical CollegeMolecular Pathology Research CenterChinese Academy of Medical SciencesBeijing 100005China

Although DNA 5-hydroxymethylcytosine(5 hmC)is recognized as an important epigenetic mark in cancer,its precise role in lymph node metastasis remains elusive.In this study,we investigated how 5 hmC associates with lymph node metastasis in breast cancer.Accompanying with high expression of TET1 and TET2 proteins,large numbers of genes in the metastasis-positive primary tumors exhibit higher 5 hmC levels than those in the metastasis-negative primary tumors.In contrast,the TET protein expression and DNA 5 hmC decrease significantly within the metastatic lesions in the lymph nodes compared to those in their matched primary tumors.Through genomewide analysis of 8 sets of primary tumors,we identified 100 high-confidence metastasis-associated5 hmC signatures,and it is found that increased levels of DNA 5 hmC and gene expression of MAP7 D1 associate with high risk of lymph node metastasis.Furthermore,we demonstrate that MAP7 D1,regulated by TET1,promotes tumor growth and metastasis.In conclusion,the dynamic5 hmC profiles during lymph node metastasis suggest a link between DNA 5 hmC and lymph node metastasis.Meanwhile,the role of MAP7 D1 in breast cancer progression suggests that the metastasis-associated 5 hmC signatures are potential biomarkers to predict the risk for lymph node metastasis,which may serve as diagnostic and therapeutic targets for metastatic breast cancer.

关键词： 5-Hydroxymethylcytosine Breast cancer Lymph node metastasis MAP7D1 Biomarker

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阿加曲班联合丁苯酞治疗急性脑梗死临床评价

中国药业 2020年第20期29卷 86-88页

作者：牛亚妹刘丽河北省石家庄市鹿泉区中医院河北石家庄050200

目的探讨阿加曲班联合丁苯酞治疗急性脑梗死的临床疗效及对患者微栓子、炎性因子与颈动脉硬化斑块的影响。方法选取医院2017年4月至2019年4月收治的急性脑梗死患者96例,随机分为观察组和对照组,各48例。两组患者均予抗血小板、改善微循... 详细信息

目的探讨阿加曲班联合丁苯酞治疗急性脑梗死的临床疗效及对患者微栓子、炎性因子与颈动脉硬化斑块的影响。方法选取医院2017年4月至2019年4月收治的急性脑梗死患者96例,随机分为观察组和对照组,各48例。两组患者均予抗血小板、改善微循环、控制血压、补充电解质平衡等基础治疗,并给予依达拉奉注射液、阿托伐他汀钙片及丁苯酞氯化钠注射液治疗,观察组患者加用阿加曲班注射液,均治疗2周。结果观察组总有效率为89.58%,显著高于对照组的72.92%(P0.05)。结论阿加曲班联合丁苯酞治疗急性脑梗死,能改善患者的神经功能、认知功能和生活质量,降低炎性因子水平,并能减少微栓子个数,缩小颈动脉硬化斑块体积。

关键词：急性脑梗死阿加曲班丁苯酞微栓子炎性因子颈动脉硬化斑块疗效

丹参多酚酸联合血塞通注射液治疗急性脑梗死临床研究

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中国药业 2020年第2期29卷 89-91页

作者：牛亚妹刘丽河北省石家庄市鹿泉区中医院

目的研究丹参多酚酸联合血塞通注射液治疗急性脑梗死的临床疗效及对患者微栓子(MES)、炎性因子与颈动脉硬化斑块的影响。方法选取医院2016年4月至2018年4月收治的急性脑梗死患者116例,按随机数字表法分为对照组和治疗组,各58例。两组患... 详细信息

目的研究丹参多酚酸联合血塞通注射液治疗急性脑梗死的临床疗效及对患者微栓子(MES)、炎性因子与颈动脉硬化斑块的影响。方法选取医院2016年4月至2018年4月收治的急性脑梗死患者116例,按随机数字表法分为对照组和治疗组,各58例。两组患者均予常规治疗,治疗组患者加用注射用丹参多酚酸和血塞通注射液,均连续治疗2周。结果治疗组总有效率为96. 55%,明显高于对照组的77. 59%(P 0. 05)。结论丹参多酚酸联合血塞通注射液治疗急性脑梗死,可明显减少MES和颈动脉硬化斑块,降低炎性因子水平。

关键词：丹参多酚酸血塞通注射液急性脑梗死微栓子炎性因子颈动脉硬化斑块临床疗效

蛋白磷酸酶2A催化亚基C在小鼠脑与阿尔茨海默病患者脑中的表达

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中华病理学杂志 2018年第9期47卷 714-718页

作者：丁菁李晴牛亚梅佟伟民中国医学科学院基础医学研究所北京协和医学院基础学院病理学系 100005 中国医学科学院神经科学中心

目的为了研究蛋白磷酸酶2A催化亚基C（PP2AC）在中枢神经系统中的功能与疾病相关性。探讨其在小鼠脑中与阿尔茨海默病患者脑中的表达情况。方法应用成年野生型小鼠全身组织、不同年龄野生型小鼠脑组织：阿尔茨海默病患者与正常人的额叶... 详细信息

目的为了研究蛋白磷酸酶2A催化亚基C（PP2AC）在中枢神经系统中的功能与疾病相关性。探讨其在小鼠脑中与阿尔茨海默病患者脑中的表达情况。方法应用成年野生型小鼠全身组织、不同年龄野生型小鼠脑组织：阿尔茨海默病患者与正常人的额叶皮质，分别制作石蜡切片和提取组织蛋白。通过免疫组织化学染色检测PP2AC在小鼠各年龄不同脑区和阿尔茨海默病患者及正常人脑样本中的表达：应用免疫印迹法检测PP2AC在小鼠全身各器官和各年龄段大脑皮质中的表达。结果在成年小鼠各器官中，PP2AC在中枢神经系统中的表达丰度最高；从胚胎第18．5天到出生后2年的小鼠脑组织中PP2AC在不同脑区呈显著的时空特异性表达模式，且PP2AC在大脑皮质呈年龄相关性表达升高的趋势。与正常人样本相比较，阿尔茨海默病患者额叶皮质中Aβ1-42表达和Tau蛋白磷酸化水平升高，而PP2AC明显减少。结论PP2AC在小鼠脑中以及在阿尔茨海默病患者脑中表达降低的时空特异性表达模式，提示PP2AC在中枢神经系统中有重要作用，且PP2AC表达下降可能与阿尔茨海默病相关。

关键词：阿尔茨海默病脑脑图年龄因素蛋白磷酸酶

RNA m6A去甲基化酶ALKBH5基因敲除对老年小鼠小脑形态和功能的影响

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中华病理学杂志 2023年第6期52卷 606-611页

作者：费祎马春卉李晴宋伟佟伟民牛亚梅中国医学科学院基础医学研究所暨北京协和医学院基础学院病理学系北京100005 中国医学科学院基础医学研究所暨北京协和医学院基础学院、医学分子生物学国家重点实验室、生物化学与分子生物学系北京100005

目的观察RNA m6A去甲基化酶ALKBH5基因敲除之后对老年小鼠小脑形态和功能的影响,探究ALKBH5在小脑退行性病变中的作用。方法免疫印迹实验检测不同年龄C57BL/6野生型小鼠(包括2月龄、6月龄、12月龄、18月龄)小脑中ALKBH5的蛋白水平。通... 详细信息

目的观察RNA m6A去甲基化酶ALKBH5基因敲除之后对老年小鼠小脑形态和功能的影响,探究ALKBH5在小脑退行性病变中的作用。方法免疫印迹实验检测不同年龄C57BL/6野生型小鼠(包括2月龄、6月龄、12月龄、18月龄)小脑中ALKBH5的蛋白水平。通过免疫组织化学实验检测中年(12月龄)及老年(18月龄)野生型小鼠和ALKBH5基因敲除(ALKBH5^(-/-))小鼠中NeuN、Calbindin-D28K、MAP2、胶质纤维酸性蛋白等蛋白的表达情况。平衡木实验和步态实验检测小鼠平衡能力以及运动协调能力。结果ALKBH5蛋白在小脑中的表达水平随着小鼠生理性衰老的进行而逐渐升高。在中年小鼠中,野生型和ALKBH5^(-/-)小鼠的体重、脑重以及小脑的形态大小没有明显差别,同时颗粒神经元、浦肯野细胞及神经元树突的形态和数量均未见明显改变。在老年小鼠中,相较于野生型小鼠,ALKBH5^(-/-)小鼠的体重、全脑重和小脑重分别下降15%、10%和21%(P<0.05)。ALKBH5在浦肯野细胞中的表达高于其他类型的神经细胞,与之对应在老年ALKBH5^(-/-)小鼠中浦肯野神经元的数量下降40%,树突的长度和密度也明显减少(P<0.01)。老年ALKBH5^(-/-)小鼠通过平衡木相较于同龄的野生型小鼠所用的时间增加70%,且出现步态不稳的情况(P<0.01)。结论RNA m6A去甲基化酶ALKBH5缺失会造成老年小鼠小脑萎缩、浦肯野神经元缺失与受损,进而损害其运动协调和平衡能力。上述结果提示RNA m6A甲基化失衡会导致小脑的神经退行性病变。

关键词：小脑浦肯野细胞 RNA m6A甲基化 ALKBH5