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Dynamic RNA Modifications in Gene Expression Regulation. ​

文献信息 ​

DOI10.1016/j.cell.2017.05.045
PMID28622506
期刊Cell
影响因子42.5
JCR 分区Q1
发表年份2017
被引次数1801
关键词RNA修饰, 基因表达调控, m6A修饰, 非编码RNA, mRNA代谢
文献类型Journal Article, Review
ISSN0092-8674
页码1187-1200
期号169(7)
作者Ian A Roundtree, Molly E Evans, Tao Pan, Chuan He

一句话小结 ​

研究表明，细胞RNA中存在超过100种化学修饰，尤其是N6-甲基腺苷（m6A）修饰在mRNA的代谢及其生命周期中发挥重要作用，这为揭示RNA修饰在细胞发育和疾病中的功能提供了新的视角。通过对编码RNA和非编码RNA修饰的深入理解，研究拓宽了遗传信息调控的层面，强调了这些动态修饰在生物学中的重要性。

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RNA修饰 · 基因表达调控 · m6A修饰 · 非编码RNA · mRNA代谢

摘要 ​

在细胞RNA中已经鉴定出超过100种化学修饰。尽管真核细胞mRNA的5'帽修饰和多（A）尾在调控中发挥着关键作用，但内部修饰因其在mRNA代谢中的作用而受到越来越多的关注。最丰富的内部mRNA修饰是N6-甲基腺苷（m6A），而识别、安装和去除这种及其他标记的蛋白质的发现揭示了mRNA修饰在几乎每个mRNA生命周期的各个方面，以及在各种细胞、发育和疾病过程中的作用。丰富的非编码RNA，如tRNA、rRNA和剪接体RNA也受到大量修饰，并依赖这些修饰进行其生物合成和功能。我们对这些不同化学修饰的生物学贡献的理解开始逐步成形，但显然，无论是在编码RNA还是非编码RNA中，动态修饰都代表着对遗传信息的一种新的控制层面。

英文摘要 ​

Over 100 types of chemical modifications have been identified in cellular RNAs. While the 5' cap modification and the poly(A) tail of eukaryotic mRNA play key roles in regulation, internal modifications are gaining attention for their roles in mRNA metabolism. The most abundant internal mRNA modification is N6-methyladenosine (m6A), and identification of proteins that install, recognize, and remove this and other marks have revealed roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes. Abundant noncoding RNAs such as tRNAs, rRNAs, and spliceosomal RNAs are also heavily modified and depend on the modifications for their biogenesis and function. Our understanding of the biological contributions of these different chemical modifications is beginning to take shape, but it's clear that in both coding and noncoding RNAs, dynamic modifications represent a new layer of control of genetic information.

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主要研究问题 ​

  1. 在不同类型的RNA中，哪些化学修饰被认为对基因表达调控最为重要？
  2. 动态RNA修饰如何影响非编码RNA的功能和生物发生过程？
  3. N6-甲基腺苷（m6A）修饰在不同细胞类型中的作用是否存在差异？
  4. 除了m6A，是否还有其他重要的RNA内部修饰在基因表达调控中扮演关键角色？
  5. RNA修饰在特定疾病状态下的变化如何影响基因表达及其相关的生物学过程？

核心洞察 ​

研究背景和目的 ​

RNA的化学修饰在基因表达调控中扮演着重要角色。尽管已有超过100种RNA化学修饰被发现，但对于内部修饰的研究相对较少。本文综述了RNA的动态修饰，尤其是N6-甲基腺苷（m6A）在mRNA代谢中的作用，探讨了这些修饰如何影响细胞过程、发育和疾病。

主要方法/材料/实验设计 ​

本研究通过以下技术路线探讨RNA修饰的动态性和功能：

Mermaid diagram
  1. 化学修饰的检测：采用高通量测序技术和分析化学方法，揭示了RNA修饰的分布和动态变化。
  2. 功能分析：通过对特定修饰的酶（如FTO和ALKBH5）的研究，探讨了这些修饰在mRNA代谢中的调控作用。

关键结果和发现 ​

  1. m6A的作用：m6A是最常见的内部修饰，影响mRNA的稳定性、翻译效率和降解速率。
  2. 修饰的酶：METTL3和METTL14复合体负责m6A的安装，而FTO和ALKBH5则参与其去甲基化。
  3. 生物学影响：m6A修饰在细胞发育、应激反应和疾病（如癌症）中发挥关键作用。

主要结论/意义/创新性 ​

本文揭示了RNA修饰，特别是m6A修饰，在基因表达调控中的重要性，提供了新的视角来理解RNA的生物学功能。这些动态修饰为细胞提供了灵活的调控机制，使其能够快速响应环境变化和生理需求。

研究局限性和未来方向 ​

  1. 研究局限性：当前对RNA修饰的理解仍然不够全面，尤其是对修饰的动态性和功能的具体机制。
  2. 未来方向：需要进一步开发高灵敏度的测序技术，以实现对RNA修饰的单碱基分辨率检测。同时，探索更多的RNA修饰及其在细胞生理和病理中的作用。

总结 ​

RNA的化学修饰为基因表达提供了新的调控层次，尤其是在细胞发育和疾病中具有重要的生物学意义。随着对这些修饰理解的深入，将为生物医学研究提供新的方向和潜在的治疗策略。

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引用本文的文献 ​

  1. Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis. - Phillip J Hsu;Yunfei Zhu;Honghui Ma;Yueshuai Guo;Xiaodan Shi;Yuanyuan Liu;Meijie Qi;Zhike Lu;Hailing Shi;Jianying Wang;Yiwei Cheng;Guanzheng Luo;Qing Dai;Mingxi Liu;Xuejiang Guo;Jiahao Sha;Bin Shen;Chuan He - Cell research (2017)
  2. A new modification for mammalian messenger RNA. - Fange Liu;Chuan He - The Journal of biological chemistry (2017)
  3. Mettl3-/Mettl14-mediated mRNA N6-methyladenosine modulates murine spermatogenesis. - Zhen Lin;Phillip J Hsu;Xudong Xing;Jianhuo Fang;Zhike Lu;Qin Zou;Ke-Jia Zhang;Xiao Zhang;Yuchuan Zhou;Teng Zhang;Youcheng Zhang;Wanlu Song;Guifang Jia;Xuerui Yang;Chuan He;Ming-Han Tong - Cell research (2017)
  4. Experience-dependent neural plasticity, learning, and memory in the era of epitranscriptomics. - L J Leighton;K Ke;E L Zajaczkowski;J Edmunds;R C Spitale;T W Bredy - Genes, brain, and behavior (2018)
  5. YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs. - Ian A Roundtree;Guan-Zheng Luo;Zijie Zhang;Xiao Wang;Tao Zhou;Yiquang Cui;Jiahao Sha;Xingxu Huang;Laura Guerrero;Phil Xie;Emily He;Bin Shen;Chuan He - eLife (2017)
  6. RMBase v2.0: deciphering the map of RNA modifications from epitranscriptome sequencing data. - Jia-Jia Xuan;Wen-Ju Sun;Peng-Hui Lin;Ke-Ren Zhou;Shun Liu;Ling-Ling Zheng;Liang-Hu Qu;Jian-Hua Yang - Nucleic acids research (2018)
  7. Role of N6-methyladenosine modification in cancer. - Xiaolan Deng;Rui Su;Xuesong Feng;Minjie Wei;Jianjun Chen - Current opinion in genetics & development (2018)
  8. Human METTL16 is a N6-methyladenosine (m6A) methyltransferase that targets pre-mRNAs and various non-coding RNAs. - Ahmed S Warda;Jens Kretschmer;Philipp Hackert;Christof Lenz;Henning Urlaub;Claudia Höbartner;Katherine E Sloan;Markus T Bohnsack - EMBO reports (2017)
  9. The impact of cellular metabolism on chromatin dynamics and epigenetics. - Michael A Reid;Ziwei Dai;Jason W Locasale - Nature cell biology (2017)
  10. Epitranscriptomic influences on development and disease. - Phillip J Hsu;Hailing Shi;Chuan He - Genome biology (2017)

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