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Post-transcriptional gene regulation by mRNA modifications. ​

文献信息 ​

DOI10.1038/nrm.2016.132
PMID27808276
期刊Nature reviews. Molecular cell biology
影响因子90.2
JCR 分区Q1
发表年份2017
被引次数1290
关键词mRNA修饰, 后转录基因调控, N6-甲基腺苷
文献类型Journal Article, Review
ISSN1471-0072
页码31-42
期号18(1)
作者Boxuan Simen Zhao, Ian A Roundtree, Chuan He

一句话小结 ​

研究发现，N6-甲基腺苷（m6A）作为一种可逆性mRNA甲基化修饰，能通过影响mRNA的代谢和翻译，指导其在细胞分化、胚胎发育及应激反应等过程中的不同命运。这一发现揭示了mRNA修饰在基因调控中的重要性，表明这些修饰共同构成了调控蛋白质合成的新信息层。

在麦伴科研 (maltsci.com) 搜索更多文献 ​

mRNA修饰 · 后转录基因调控 · N6-甲基腺苷

摘要 ​

最近可逆性mRNA甲基化的发现开启了真核生物转录后基因调控的新领域。特异性识别RNA N6-甲基腺苷（m6A）的蛋白质的鉴定和功能特征分析揭示了这种修饰是细胞用来加速mRNA代谢和翻译的方式。N6-腺苷甲基化通过将mRNA分组以实现差异处理、翻译和降解，指引它们走向不同的命运，参与细胞分化、胚胎发育和应激反应等过程。其他mRNA修饰，包括N1-甲基腺苷（m1A）、5-甲基胞嘧啶（m5C）和假尿苷，与m6A共同形成了表转录组， collectively 编码了控制蛋白质合成的新信息层。

英文摘要 ​

The recent discovery of reversible mRNA methylation has opened a new realm of post-transcriptional gene regulation in eukaryotes. The identification and functional characterization of proteins that specifically recognize RNA N6-methyladenosine (m6A) unveiled it as a modification that cells utilize to accelerate mRNA metabolism and translation. N6-adenosine methylation directs mRNAs to distinct fates by grouping them for differential processing, translation and decay in processes such as cell differentiation, embryonic development and stress responses. Other mRNA modifications, including N1-methyladenosine (m1A), 5-methylcytosine (m5C) and pseudouridine, together with m6A form the epitranscriptome and collectively code a new layer of information that controls protein synthesis.

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主要研究问题 ​

  1. mRNA的不同修饰如何具体影响细胞的命运和功能？
  2. 在不同的生理和病理状态下，m6A修饰的动态变化是如何影响基因表达的？
  3. 除了m6A，其他mRNA修饰如m1A和m5C在基因调控中扮演什么角色？
  4. 目前已知的与mRNA修饰相关的蛋白质有哪些，它们的具体功能是什么？
  5. 如何利用mRNA修饰的知识开发新的治疗策略来应对疾病？

核心洞察 ​

研究背景和目的 ​

随着可逆性mRNA甲基化的发现，后转录基因调控的研究进入了新的领域。N6-甲基腺苷（m6A）作为最丰富的内部修饰，能够加速mRNA的代谢和翻译，对细胞分化、胚胎发育和应激反应等过程具有重要影响。本文旨在探讨m6A及其他mRNA修饰在基因表达调控中的作用。

主要方法/材料/实验设计 ​

本研究采用了以下主要技术路线：

Mermaid diagram
  • m6A的沉积：由多组分甲基转移酶复合体负责，包括METTL3、METTL14、WTAP和KIAA1429等。
  • m6A的去甲基化：通过FTO和ALKBH5去除m6A。
  • m6A的识别：由阅读蛋白（如YTHDF家族和HNRNP蛋白）介导，调控mRNA的翻译和降解。

关键结果和发现 ​

  1. m6A的分布和功能：在超过25%的人类转录本中发现了超过10,000个m6A位点，主要集中在长外显子、停止密码子附近和3'非翻译区（3' UTR）。
  2. m6A对mRNA代谢的影响：
    • 加工：m6A参与mRNA的剪接，促进成品mRNA的形成。
    • 核出口：m6A修饰促进mRNA从细胞核转运到细胞质。
    • 翻译：m6A通过直接结合翻译起始因子，增强mRNA的翻译效率。
    • 降解：m6A标记的mRNA更易于被降解，参与调控基因表达的时效性。

主要结论/意义/创新性 ​

m6A作为一种动态的RNA修饰，不仅调控mRNA的代谢，还在细胞分化、应激反应等生物过程中发挥关键作用。研究表明，m6A的可逆性和分布模式为细胞提供了灵活的基因表达调控机制，可能影响细胞的命运和功能。

研究局限性和未来方向 ​

尽管本研究揭示了m6A在基因调控中的重要性，但仍存在以下局限性：

  • 对其他mRNA修饰（如m1A、m5C和假尿苷）的理解不足。
  • 需要进一步研究m6A与其他信号通路的交互作用。

未来的研究方向应集中在：

  • 深入探讨mRNA化学修饰的生物功能及其调控机制。
  • 开发新的技术以精确定位和定量这些修饰在不同生物学过程中的作用。

参考文献 ​

  1. Sequences containing methylated nucleotides at the 5' termini of messenger RNAs: possible implications for processing. - F Rottman;A J Shatkin;R P Perry - Cell (1974)
  2. High-resolution N(6) -methyladenosine (m(6) A) map using photo-crosslinking-assisted m(6) A sequencing. - Kai Chen;Zhike Lu;Xiao Wang;Ye Fu;Guan-Zheng Luo;Nian Liu;Dali Han;Dan Dominissini;Qing Dai;Tao Pan;Chuan He - Angewandte Chemie (International ed. in English) (2015)
  3. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. - Xu Zhao;Ying Yang;Bao-Fa Sun;Yue Shi;Xin Yang;Wen Xiao;Ya-Juan Hao;Xiao-Li Ping;Yu-Sheng Chen;Wen-Jia Wang;Kang-Xuan Jin;Xing Wang;Chun-Min Huang;Yu Fu;Xiao-Meng Ge;Shu-Hui Song;Hyun Seok Jeong;Hiroyuki Yanagisawa;Yamei Niu;Gui-Fang Jia;Wei Wu;Wei-Min Tong;Akimitsu Okamoto;Chuan He;Jannie M Rendtlew Danielsen;Xiu-Jie Wang;Yun-Gui Yang - Cell research (2014)
  4. N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. - Xiao Wang;Boxuan Simen Zhao;Ian A Roundtree;Zhike Lu;Dali Han;Honghui Ma;Xiaocheng Weng;Kai Chen;Hailing Shi;Chuan He - Cell (2015)
  5. Molecular basis for the recognition of methylated adenines in RNA by the eukaryotic YTH domain. - Shukun Luo;Liang Tong - Proceedings of the National Academy of Sciences of the United States of America (2014)
  6. Polymorphisms in FTO and near TMEM18 associate with type 2 diabetes and predispose to younger age at diagnosis of diabetes. - Ineta Kalnina;Linda Zaharenko;Iveta Vaivade;Vita Rovite;Liene Nikitina-Zake;Raitis Peculis;Davids Fridmanis;Kristine Geldnere;Josefin A Jacobsson;Markus S Almen;Valdis Pirags;Helgi B Schiöth;Janis Klovins - Gene (2013)
  7. Landscape and variation of RNA secondary structure across the human transcriptome. - Yue Wan;Kun Qu;Qiangfeng Cliff Zhang;Ryan A Flynn;Ohad Manor;Zhengqing Ouyang;Jiajing Zhang;Robert C Spitale;Michael P Snyder;Eran Segal;Howard Y Chang - Nature (2014)
  8. tRNA modifications regulate translation during cellular stress. - Chen Gu;Thomas J Begley;Peter C Dedon - FEBS letters (2014)
  9. The protective effect of the obesity-associated rs9939609 A variant in fat mass- and obesity-associated gene on depression. - Z Samaan;S S Anand;S Anand;X Zhang;D Desai;M Rivera;G Pare;L Thabane;C Xie;H Gerstein;J C Engert;I Craig;S Cohen-Woods;V Mohan;R Diaz;X Wang;L Liu;T Corre;M Preisig;Z Kutalik;S Bergmann;P Vollenweider;G Waeber;S Yusuf;D Meyre - Molecular psychiatry (2013)
  10. Association of type 2 diabetes susceptibility variants with advanced prostate cancer risk in the Breast and Prostate Cancer Cohort Consortium. - Mitchell J Machiela;Sara Lindström;Naomi E Allen;Christopher A Haiman;Demetrius Albanes;Aurelio Barricarte;Sonja I Berndt;H Bas Bueno-de-Mesquita;Stephen Chanock;J Michael Gaziano;Susan M Gapstur;Edward Giovannucci;Brian E Henderson;Eric J Jacobs;Laurence N Kolonel;Vittorio Krogh;Jing Ma;Meir J Stampfer;Victoria L Stevens;Daniel O Stram;Anne Tjønneland;Ruth Travis;Walter C Willett;David J Hunter;Loic Le Marchand;Peter Kraft - American journal of epidemiology (2012)

引用本文的文献 ​

  1. Reversible RNA modifications in meiosis and pluripotency. - Arne Klungland;John Arne Dahl;Gareth Greggains;Peter Fedorcsak;Adam Filipczyk - Nature methods (2016)
  2. Pseudouridine and N6-methyladenosine modifications weaken PUF protein/RNA interactions. - Pavanapuresan P Vaidyanathan;Ishraq AlSadhan;Dawn K Merriman;Hashim M Al-Hashimi;Daniel Herschlag - RNA (New York, N.Y.) (2017)
  3. SR Proteins: Binders, Regulators, and Connectors of RNA. - Sunjoo Jeong - Molecules and cells (2017)
  4. NSUN2-Mediated m5C Methylation and METTL3/METTL14-Mediated m6A Methylation Cooperatively Enhance p21 Translation. - Qiu Li;Xiu Li;Hao Tang;Bin Jiang;Yali Dou;Myriam Gorospe;Wengong Wang - Journal of cellular biochemistry (2017)
  5. Antibodies specific for nucleic acid modifications. - Regina Feederle;Aloys Schepers - RNA biology (2017)
  6. RNA modifications go viral. - Nandan S Gokhale;Stacy M Horner - PLoS pathogens (2017)
  7. Chemical and Conformational Diversity of Modified Nucleosides Affects tRNA Structure and Function. - Ville Y P Väre;Emily R Eruysal;Amithi Narendran;Kathryn L Sarachan;Paul F Agris - Biomolecules (2017)
  8. The Epitranscriptome of Noncoding RNAs in Cancer. - Manel Esteller;Pier Paolo Pandolfi - Cancer discovery (2017)
  9. A fly view on the roles and mechanisms of the m6A mRNA modification and its players. - Tina Lence;Matthias Soller;Jean-Yves Roignant - RNA biology (2017)
  10. X chromosome inactivation: new players in the initiation of gene silencing. - Ines Pinheiro;Edith Heard - F1000Research (2017)

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