文献精选 > 高引权威"mRNA疫苗"文献

N6-methyladenosine-dependent regulation of messenger RNA stability.

文献信息

DOI	10.1038/nature12730
PMID	24284625
期刊	Nature
影响因子	48.5
JCR 分区	Q1
发表年份	2014
被引次数	2446
关键词	N6-甲基腺苷, 信使RNA稳定性, YTHDF2
文献类型	Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.
ISSN	0028-0836
页码	117-20
期号	505(7481)
作者	Xiao Wang, Zhike Lu, Adrian Gomez, Gary C Hon, Yanan Yue, Dali Han, Ye Fu, Marc Parisien, Qing Dai, Guifang Jia, Bing Ren, Tao Pan, Chuan He

一句话小结

本研究揭示了N(6)-甲基腺苷（m(6)A）修饰在哺乳动物细胞中通过YTHDF2蛋白选择性调节mRNA降解的机制，识别出3000多个YTHDF2靶标RNA，并阐明其在RNA代谢中的关键作用。该发现不仅加深了对m(6)A在基因表达调控中的理解，也为研究其在疾病中的潜在影响提供了重要线索。

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N6-甲基腺苷 · 信使RNA稳定性 · YTHDF2

摘要

N(6)-甲基腺苷（m(6)A）是所有高等真核生物的信使RNA中最常见的内部（非帽）修饰。尽管对细胞的生存和发育至关重要，但m(6)A修饰的确切作用尚待确定。最近在哺乳动物细胞中发现的两种m(6)A去甲基化酶突显了m(6)A在基本生物功能和疾病中的重要性。在本研究中，我们展示了m(6)A被人类YTH结构域家族2（YTHDF2）“读者”蛋白选择性识别，从而调节mRNA的降解。我们鉴定出YTHDF2的3000多个细胞RNA靶标，其中大多数为mRNA，但也包括非编码RNA，具有保守的核心基序G(m(6)A)C。我们进一步确立了YTHDF2在RNA代谢中的作用，表明YTHDF2的结合导致结合的mRNA从可翻译池定位到mRNA降解位点，如处理体。YTHDF2的羧基末端结构域选择性结合含m(6)A的mRNA，而氨基末端结构域则负责将YTHDF2-mRNA复合物定位到细胞RNA降解位点。我们的结果表明，动态的m(6)A修饰通过选择性结合蛋白质的识别，影响mRNA的翻译状态和寿命。

英文摘要

N(6)-methyladenosine (m(6)A) is the most prevalent internal (non-cap) modification present in the messenger RNA of all higher eukaryotes. Although essential to cell viability and development, the exact role of m(6)A modification remains to be determined. The recent discovery of two m(6)A demethylases in mammalian cells highlighted the importance of m(6)A in basic biological functions and disease. Here we show that m(6)A is selectively recognized by the human YTH domain family 2 (YTHDF2) 'reader' protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m(6)A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies. The carboxy-terminal domain of YTHDF2 selectively binds to m(6)A-containing mRNA, whereas the amino-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m(6)A modification is recognized by selectively binding proteins to affect the translation status and lifetime of mRNA.

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主要研究问题

1. N6-methyladenosine的修饰如何具体影响mRNA的翻译过程？
2. 在不同细胞类型中，YTHDF2对mRNA稳定性的调控是否存在差异？
3. 除了YTHDF2，还有哪些蛋白质参与m(6)A修饰的识别和调控？
4. m(6)A修饰在肿瘤发展中扮演了怎样的角色，是否可以作为治疗靶点？
5. 如何利用m(6)A修饰的特性开发新的基因表达调控工具？

核心洞察

研究背景和目的

N6-甲基腺苷（m6A）是高等真核生物信使RNA（mRNA）中最常见的内部修饰。尽管m6A在细胞生存和发育中至关重要，但其具体功能仍不明确。本研究旨在探讨m6A修饰如何通过选择性结合蛋白（YTHDF2）调控mRNA的降解。

主要方法/材料/实验设计

本研究采用了多种实验技术来研究YTHDF2与m6A的相互作用和mRNA的降解机制，主要包括：

1. YTHDF2的识别和结合：通过使用m6A修饰的RNA探针进行拉下实验，确认YTHDF2选择性结合m6A修饰的mRNA。
2. 高通量测序：应用PAR-CLIP和RIP-seq技术识别YTHDF2的结合目标RNA。
3. mRNA寿命分析：通过RNA-seq和转录抑制剂（如秋水仙碱）评估YTHDF2敲低对mRNA寿命的影响。
4. ribosome profiling：评估mRNA的翻译效率。

关键结果和发现

1. YTHDF2选择性结合m6A：YTHDF2能够选择性地结合m6A修饰的mRNA，且其结合位点主要集中在mRNA的3'非翻译区和编码区。
2. 调控mRNA降解：YTHDF2的结合促进了m6A含量mRNA的降解，敲低YTHDF2后，其目标mRNA的寿命延长约30%。
3. 翻译效率降低：YTHDF2的缺失导致目标mRNA的翻译效率降低，表现为mRNA积累而非翻译的状态增加。

主要结论/意义/创新性

本研究首次功能性证明了m6A“读者”蛋白YTHDF2在mRNA降解中的重要作用。YTHDF2通过选择性识别m6A修饰的mRNA，调节其稳定性和翻译状态，为理解m6A在基因表达调控中的作用提供了新视角。

研究局限性和未来方向

本研究的局限性包括：

• 主要在HeLa细胞中进行，缺乏在其他细胞类型或生理条件下的验证。
• 对于YTHDF2调控的具体分子机制仍需进一步探讨。

未来的研究方向可以包括：

• 探索其他m6A结合蛋白的功能。
• 研究m6A在不同生理和病理状态下的调控作用。
• 评估YTHDF2在疾病（如癌症）中的潜在应用。

参考文献

1. Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability. - Neelanjan Mukherjee;David L Corcoran;Jeffrey D Nusbaum;David W Reid;Stoyan Georgiev;Markus Hafner;Manuel Ascano;Thomas Tuschl;Uwe Ohler;Jack D Keene - Molecular cell (2011)
2. Grand challenge commentary: RNA epigenetics? - Chuan He - Nature chemical biology (2010)
3. A quantitative analysis of CLIP methods for identifying binding sites of RNA-binding proteins. - Shivendra Kishore;Lukasz Jaskiewicz;Lukas Burger;Jean Hausser;Mohsen Khorshid;Mihaela Zavolan - Nature methods (2011)
4. Induction of sporulation in Saccharomyces cerevisiae leads to the formation of N6-methyladenosine in mRNA: a potential mechanism for the activity of the IME4 gene. - Mary J Clancy;Mary Eileen Shambaugh;Candace S Timpte;Joseph A Bokar - Nucleic acids research (2002)
5. Decapping and decay of messenger RNA occur in cytoplasmic processing bodies. - Ujwal Sheth;Roy Parker - Science (New York, N.Y.) (2003)
6. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. - Dan Dominissini;Sharon Moshitch-Moshkovitz;Schraga Schwartz;Mali Salmon-Divon;Lior Ungar;Sivan Osenberg;Karen Cesarkas;Jasmine Jacob-Hirsch;Ninette Amariglio;Martin Kupiec;Rotem Sorek;Gideon Rechavi - Nature (2012)
7. Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons. - Kate D Meyer;Yogesh Saletore;Paul Zumbo;Olivier Elemento;Christopher E Mason;Samie R Jaffrey - Cell (2012)
8. Immunoprecipitation of mRNA-protein complexes. - Tiina Peritz;Fanyi Zeng;Theresa J Kannanayakal;Kalle Kilk;Emelía Eiríksdóttir;Ulo Langel;James Eberwine - Nature protocols (2006)
9. The formation of internal 6-methyladenine residues in eucaryotic messenger RNA. - M T Tuck - The International journal of biochemistry (1992)
10. Y14 and hUpf3b form an NMD-activating complex. - Niels H Gehring;Gabriele Neu-Yilik;Thomas Schell;Matthias W Hentze;Andreas E Kulozik - Molecular cell (2003)

引用本文的文献

1. RNA: The (methylation) reader. - Kim Baumann - Nature reviews. Molecular cell biology (2014)
2. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. - Xiao-Li Ping;Bao-Fa Sun;Lu Wang;Wen Xiao;Xin Yang;Wen-Jia Wang;Samir Adhikari;Yue Shi;Ying Lv;Yu-Sheng Chen;Xu Zhao;Ang Li;Ying Yang;Ujwal Dahal;Xiao-Min Lou;Xi Liu;Jun Huang;Wei-Ping Yuan;Xiao-Fan Zhu;Tao Cheng;Yong-Liang Zhao;Xinquan Wang;Jannie M Rendtlew Danielsen;Feng Liu;Yun-Gui Yang - Cell research (2014)
3. Methyltransferases modulate RNA stability in embryonic stem cells. - Shuibin Lin;Richard I Gregory - Nature cell biology (2014)
4. Nucleic acid oxidation in DNA damage repair and epigenetics. - Guanqun Zheng;Ye Fu;Chuan He - Chemical reviews (2014)
5. Gene expression regulation mediated through reversible m⁶A RNA methylation. - Ye Fu;Dan Dominissini;Gideon Rechavi;Chuan He - Nature reviews. Genetics (2014)
6. The dynamic epitranscriptome: N6-methyladenosine and gene expression control. - Kate D Meyer;Samie R Jaffrey - Nature reviews. Molecular cell biology (2014)
7. Genome-wide mapping of cellular protein-RNA interactions enabled by chemical crosslinking. - Xiaoyu Li;Jinghui Song;Chengqi Yi - Genomics, proteomics & bioinformatics (2014)
8. RNA epigenetics. - Nian Liu;Tao Pan - Translational research : the journal of laboratory and clinical medicine (2015)
9. Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N6-methyladenosine RNA demethylation. - Chao Xu;Ke Liu;Wolfram Tempel;Marina Demetriades;WeiShen Aik;Christopher J Schofield;Jinrong Min - The Journal of biological chemistry (2014)
10. Reading RNA methylation codes through methyl-specific binding proteins. - Xiao Wang;Chuan He - RNA biology (2014)

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