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浙江大学学报(医学版)  2021, Vol. 50 Issue (5): 642-650    DOI: 10.3724/zdxbyxb-2021-0160
综述     
表观遗传修饰在神经退行性变性疾病中的作用研究进展
曲文政1,庄英粮1,2,李学坤1,2,*()
1.浙江大学医学院附属儿童医院 国家儿童健康与疾病临床医学研究中心 国家儿童区域医疗中心,浙江 杭州 310052
2.浙江大学转化医学研究院,浙江 杭州 310029
The roles of epigenetic modifications in neurodegenerative diseases
QU Wenzheng1,ZHUANG Yingliang1,2,LI Xuekun1,2,*()
1. Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou 310052, China;
2. Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China
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摘要:

表观遗传修饰对神经发育、神经干细胞命运决定和神经系统的生理功能发挥具有重要的调节作用。异常的表观遗传修饰与阿尔茨海默病、帕金森病和亨廷顿病等神经退行性变性疾病的发生和发展有密切关系:异常升高的DNA甲基化修饰抑制了一些修复基因的表达,影响亨廷顿病进展;阿尔茨海默病患者大脑中H3K27ac和H3K9ac组蛋白修饰增加,影响神经变性;RNA甲基化修饰在阿尔茨海默病和帕金森病两种疾病动物模型中呈现差异化的改变。因此,表观遗传修饰可能作为神经系统疾病的潜在治疗靶点。本文综述了表观遗传修饰参与神经退行性变性疾病及其分子机制的最新研究进展。

关键词: 表观遗传学DNA修饰组蛋白修饰RNA修饰阿尔茨海默病帕金森病亨廷顿病综述    
Abstract:

In neuronal system, epigenetic modifications are essential for neuronal development, the fate determination of neural stem cells and neuronal function. The dysfunction of epigenetic regulation is closely related to occurrence and development of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease. Abnormally elevated DNA methylation inhibits the expression of some DNA repair-related genes and affects the progression of Huntington’s disease. In the brain of Alzheimer’s disease patients, the levels of H3K27ac and H3K9ac histone modifications increased. In addition, the alteration of RNA methylation in animal models of Alzheimer’s disease and Parkinson’s disease showed discrepancy trends. Therefore, epigenetic modifications may serve as potential therapeutic targets for neurodegenerative diseases. Here, we summarize the recent progress of the roles of epigenetic modifications in neurodegenerative diseases.

Key words: Epigenetics    DNA modification    Histone modification    RNA modification    Alzheimer’s disease    Parkinson’s disease    Huntington’s disease    Review
收稿日期: 2021-06-04 出版日期: 2021-12-29
:  R394  
基金资助: 国际科技合作重点项目计划(YS2017YFGH001214),国家自然科学基金(92049108)
通讯作者: 李学坤     E-mail: xuekun_li@zju.edu.cn
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引用本文:

曲文政,庄英粮,李学坤. 表观遗传修饰在神经退行性变性疾病中的作用研究进展[J]. 浙江大学学报(医学版), 2021, 50(5): 642-650.

QU Wenzheng,ZHUANG Yingliang,LI Xuekun. The roles of epigenetic modifications in neurodegenerative diseases. J Zhejiang Univ (Med Sci), 2021, 50(5): 642-650.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2021-0160        https://www.zjujournals.com/med/CN/Y2021/V50/I5/642

图 1  组蛋白乙酰化与甲基化修饰、DNA修饰和RNA mA甲基化修饰示意图6组蛋白甲基化由组蛋白甲基化酶(HMT)与组蛋白去甲基化酶(HDM)两大类酶调控,组蛋白乙酰化由组蛋白乙酰化酶(HAT)和组蛋白脱乙酰酶(HDAC)调控.组蛋白甲基化或乙酰化修饰异常影响基因的转录表达.DNA甲基化修饰是胞嘧啶在DNA甲基化酶(DNMT)的作用下转化成5-甲基胞嘧啶(5mC).DNA5-羟甲基化修饰是在5mC去甲基化过程中,在TET作用下转化成5-羟甲基胞嘧啶(5hmC).5hmC可在TET和胸腺嘧啶DNA糖基化酶(TDG)的作用下,经碱基切除修复(BER)转化成胞嘧啶.RNA N6-甲基腺苷(mA)甲基化由“writers”、“erasers”和“readers”蛋白调控,其中“writers”是RNA甲基化酶,包括甲基转移酶样(METTL)3和METTL14等,“erasers”是RNA去甲基化酶,包括FTO和ALKBH5,“readers”包括YTHDF1/2/3等,调节RNA转运、剪切、翻译等.
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