m 6A修饰对中枢神经系统功能及疾病的影响

doi:10.16288/j.yczz.20-233

遗传 ›› 2020, Vol. 42 ›› Issue (12): 1156-1167.doi: 10.16288/j.yczz.20-233

m ⁶A修饰对中枢神经系统功能及疾病的影响

史佳宾^1,^2,³, 王大勇^1,^2,³, 夏晴^1,^2,³, 高旭^1,^2,³()

^1. 哈尔滨医科大学基础医学院生物化学与分子生物学教研室,哈尔滨 150081
^2. 哈尔滨医科大学北方转化医学研究合作中心,哈尔滨 150081
^3. 黑龙江省医学科学院,哈尔滨 150081

收稿日期:2020-07-21 修回日期:2020-10-21 出版日期:2020-12-17 发布日期:2020-10-28
通讯作者: 高旭 E-mail:gaoxu_671227@163.com
基金资助:
国家自然科学基金项目编号(81701078);国家自然科学基金项目编号(81773165);黑龙江省自然科学基金项目编号(QC2017090);黑龙江省普通本科高等学校青年创新人才培养计划项目编号(UNPYSCT-2016190);中国博士后科学基金(面上资助)项目编号(2016M600261);中国博士后科学基金(特别资助)项目编号(2018T110317);哈尔滨医科大学校创新科学研究资助项目编号(2016JCZX37);黑龙江省博士后经费项目资助编号(LBH-Z15163)

The effects of m ⁶A modification in central nervous system function and disease

Jiabin Shi^1,^2,³, Dayong Wang^1,^2,³, Qing Xia^1,^2,³, Xu Gao^1,^2,³()

^1. Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin 150081, China
^2. Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, Harbin 150081, China
^3. Heilongjiang Academy of Medical Sciences, Harbin 150081, China

Received:2020-07-21 Revised:2020-10-21 Online:2020-12-17 Published:2020-10-28
Contact: Gao Xu E-mail:gaoxu_671227@163.com
Supported by:
Supported by the National Natural Science Foundation of China Nos(81701078);Supported by the National Natural Science Foundation of China Nos(81773165);Natural Science Foundation of Heilongjiang Province of China No(QC2017090);the University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province No(UNPYSCT-2016190);China Postdoctoral Science Foundation Nos(2016M600261);China Postdoctoral Science Foundation Nos(2018T110317);the Innovative Science Research Project of Harbin Medical University No(2016JCZX37);Heilongjiang Postdoctoral Financial Assistance No(LBH-Z15163)

摘要/Abstract

摘要：

6-甲基腺嘌呤(N ⁶-methyladenosine, m ⁶A)是一种重要的RNA修饰,参与细胞内mRNA的整个代谢活动,调控基因的表达,调节多种生物过程,在大脑组织中丰度较高。稳定的m ⁶A修饰有助于胚胎大脑发育、记忆力的形成,在维持中枢神经系统的功能中起到重要作用。当m ⁶A修饰水平及相关蛋白表达水平发生改变时,将会引起神经系统功能异常,包括脑组织发育迟缓、轴突再生能力障碍、记忆力改变以及干细胞更新和分化紊乱等。近年来的研究还发现,m ⁶A修饰及其相关蛋白在阿尔茨海默症、帕金森症、脆性X染色体综合征、抑郁症和胶质母细胞瘤等众多神经系统疾病的发展进程中扮演关键角色。本文主要综述了近年来在中枢神经系统中m ⁶A修饰调控机制研究的相关进展,重点介绍了m ⁶A修饰介导的基因表达调控对中枢神经系统生物学功能以及多种相关疾病的影响,以期为中枢神经系统疾病提供新的研究靶点和治疗方向。

关键词: 6-甲基腺嘌呤(m ⁶A), 中枢神经系统, 干细胞, 突触, 记忆

Abstract:

N ⁶-methyladenosine (m ⁶A) is an important RNA modification, which is highly active in brain tissues, participates in global intracellular mRNA metabolism, and regulates gene expression and a variety of biological processes. Stable m ⁶A modification contributes to the normal embryonic brain development and memory formation and plays an important role in maintaining the functions of the central nervous system. However, changes in the level of m ⁶A modification and the expression of its related proteins cause abnormal nervous system functions, including brain tissue development retardation, axon regeneration disorders, memory changes, and stem cell renewal and differentiation disorders. Recent studies have also found that m ⁶A modification and its related proteins play key roles in the development of various nervous system diseases, such as Alzheimer's disease, Parkinson's disease, fragile X-chromosome syndrome, depression and glioblastoma. In this review, we summarize the research progresses of m ⁶A modification regulation mechanism in the central nervous system in recent years, and discusses the effects of gene expression regulation mediated by m ⁶A modification on the biological functions of the central nervous system and related diseases, thereby providing some insights on the new research targets and treatment directions for the central nervous system diseases.

Key words: N ⁶-methyladenosine (m ⁶A), central nervous system, stem cell, synapse, memory

史佳宾, 王大勇, 夏晴, 高旭. m ⁶A修饰对中枢神经系统功能及疾病的影响[J]. 遗传, 2020, 42(12): 1156-1167.

Jiabin Shi, Dayong Wang, Qing Xia, Xu Gao. The effects of m ⁶A modification in central nervous system function and disease[J]. Hereditas(Beijing), 2020, 42(12): 1156-1167.

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类别	基因	功能	作用	参考文献
甲基化转移酶 (Writers)	METTL3	影响Dapk1、Fadd、Ngfr的mRNA半衰期	METTL3缺失可使m⁶A修饰异常,导致小脑发育不全、长期记忆能力减弱,影响干细胞的自我更新和分化	[10]
	METTL14	识别并影响Pten蛋白的翻译	METTL14敲除可影响轴突再生能力	[11]
	ZC3h13	ZC3h13使Zc3h13-WTAP-Virilizer-Hakai复合物留在核内,提高mESC内的mRNA m⁶A修饰水平	ZC3h13敲除将导致复合物从细胞核转移到细胞质,使m⁶A水平降低,破坏mESC自我更新并诱导进行分化	[12]
去甲基化转移酶 (Erasers)	FTO	FTO可抑制突触神经节中Syp基因mRNA的转录,降低Spy的蛋白水平	降低FTO的表达后可提高Syp蛋白水平,从而提高记忆能力	[13]
识别蛋白 (Readers)	YTHDF1	YTHDF1识别并结合发生m⁶A修饰的GRIN1、GRIN2A、GRIA1、CAMK2A、CAMK2B基因的mRNA,促进翻译过程	YTHDF1缺失引起相关蛋白的翻译异常,导致记忆力下降	[14]
识别蛋白 (Readers)	YTHDF3	YTHDF3可特异性识别胞浆中发生m⁶A修饰的Apc基因mRNA,与YTHDF1共同调控翻译过程	YTHDF1和YTHDF3缺失引起Apc蛋白翻译异常,可导致神经元发育异常,突触传递能力降低	[15]

m ⁶A修饰对中枢神经系统功能及疾病的影响

The effects of m ⁶A modification in central nervous system function and disease

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