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文献精选 > 近年高分"阿尔茨海默病"研究（IF≥30，近5年）

Epigenetic and epitranscriptomic regulation of viral replication. ​

文献信息 ​

DOI10.1038/s41579-020-0382-3
PMID32533130
期刊Nature reviews. Microbiology
影响因子103.3
JCR 分区Q1
发表年份2020
被引次数93
关键词表观遗传学, 病毒复制, 转录后修饰
文献类型Journal Article, Research Support, N.I.H., Extramural, Review
ISSN1740-1526
页码559-570
期号18(10)
作者Kevin Tsai, Bryan R Cullen

一句话小结 ​

本研究综述了真核生物基因表达受到染色质和RNA共价修饰的影响，尤其是组蛋白H3的表观遗传修饰如何增强或抑制病毒基因表达，同时探讨了病毒进化出的对策以规避这些修饰。该研究强调染色质和RNA修饰作为开发抗病毒药物的新靶点的重要性，为理解病毒感染机制提供了新的视角。

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表观遗传学 · 病毒复制 · 转录后修饰

摘要 ​

真核生物基因表达不仅受到基因组增强子和启动子的调控，还受到附加在染色质和RNA上的共价修饰的影响。细胞基因表达可能因特定的表观遗传修饰（特别是组蛋白H3）而增强或抑制，这些表观遗传修饰也可以抑制病毒基因的表达，可能作为DNA病毒感染细胞中的一种强效抗病毒先天免疫反应。然而，病毒已经进化出对策，以防止其基因在裂解复制过程中的表观遗传沉默，同时它们也能够利用表观遗传沉默来建立潜伏感染。相反，添加到RNA上的各种共价修饰，被称为表转录组修饰，可以积极调控mRNA的翻译和/或稳定性，DNA和RNA病毒均已进化出利用表转录组修饰的机制，以最大化病毒基因的表达。因此，染色质和RNA的修饰可以作为开发抗病毒药物的新靶点。在本综述中，我们讨论了宿主的表观遗传和表转录组过程如何在染色质和RNA功能层面上调控病毒基因表达，并探讨了病毒如何修改、规避或利用这些过程来调控病毒基因表达。

英文摘要 ​

Eukaryotic gene expression is regulated not only by genomic enhancers and promoters, but also by covalent modifications added to both chromatin and RNAs. Whereas cellular gene expression may be either enhanced or inhibited by specific epigenetic modifications deposited on histones (in particular, histone H3), these epigenetic modifications can also repress viral gene expression, potentially functioning as a potent antiviral innate immune response in DNA virus-infected cells. However, viruses have evolved countermeasures that prevent the epigenetic silencing of their genes during lytic replication, and they can also take advantage of epigenetic silencing to establish latent infections. By contrast, the various covalent modifications added to RNAs, termed epitranscriptomic modifications, can positively regulate mRNA translation and/or stability, and both DNA and RNA viruses have evolved to utilize epitranscriptomic modifications as a means to maximize viral gene expression. As a consequence, both chromatin and RNA modifications could serve as novel targets for the development of antivirals. In this Review, we discuss how host epigenetic and epitranscriptomic processes regulate viral gene expression at the levels of chromatin and RNA function, respectively, and explore how viruses modify, avoid or utilize these processes in order to regulate viral gene expression.

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主要研究问题 ​

  1. 如何不同类型的病毒利用表观遗传和转录后修饰来增强其基因表达？
  2. 表观遗传修饰在宿主细胞中如何影响病毒的潜伏感染与再激活？
  3. 在开发抗病毒药物时，如何针对表观遗传和转录后修饰的靶点进行设计？
  4. 表观遗传调控和转录后修饰在病毒生命周期的不同阶段扮演什么样的角色？
  5. 目前有哪些研究表明表观遗传机制在抗病毒免疫反应中的重要性？

核心洞察 ​

研究背景和目的 ​

在真核生物中，基因表达受到多种机制的调控，包括表观遗传修饰和转录后修饰。特别是，病毒在宿主细胞中复制时，能够利用宿主的表观遗传和转录后修饰机制来调控其基因表达。本文旨在探讨宿主细胞如何通过表观遗传和转录后修饰过程调控病毒基因表达，以及病毒如何利用或逃避这些机制以增强自身的复制能力。

主要方法/材料/实验设计 ​

研究主要采用文献综述的方法，结合已有的实验数据，探讨表观遗传和转录后修饰在病毒复制中的作用。研究重点包括：

  • 表观遗传调控机制：包括DNA甲基化、组蛋白修饰、染色质重塑等。
  • 转录后修饰机制：主要关注RNA的修饰，如N6-甲基腺苷(m6A)、5-甲基胞苷(m5C)、N4-乙酰胞苷(ac4C)和2'-O-甲基化(Nm)。

以下是技术路线的流程图表示：

Mermaid diagram

关键结果和发现 ​

  1. 表观遗传调控：

    • 宿主细胞通过表观遗传机制对病毒DNA进行抑制，主要依赖于PML-NB和IFI16等蛋白。
    • 病毒通过编码或包装特定的蛋白质（如HSV-1的VP16和ICP0）来逃避这种抑制。

  2. 转录后修饰：

    • 病毒RNA中发现高水平的m6A、m5C和Nm修饰，这些修饰增强了病毒的mRNA稳定性和翻译效率。
    • m6A修饰能够帮助病毒逃避宿主的免疫监测，促进病毒复制。

主要结论/意义/创新性 ​

研究表明，表观遗传和转录后修饰不仅是宿主细胞对病毒的免疫反应机制，也是病毒适应和逃避宿主免疫的重要策略。这些发现为抗病毒药物的开发提供了新的靶点，特别是在利用表观遗传和转录后修饰来抑制病毒复制方面。

研究局限性和未来方向 ​

尽管研究揭示了表观遗传和转录后修饰在病毒复制中的重要性，但关于如何区分宿主DNA和病毒DNA的机制仍不明确。此外，转录后修饰的读者和写入机制仍需进一步研究。未来的研究可以集中在开发针对这些修饰的抗病毒药物，以及探讨这些修饰在不同病毒感染中的具体作用和机制。

参考文献 ​

  1. Perceiving the epigenetic landscape through histone readers. - Catherine A Musselman;Marie-Eve Lalonde;Jacques Côté;Tatiana G Kutateladze - Nature structural & molecular biology (2012)
  2. Editing the Epigenome: Reshaping the Genomic Landscape. - Liad Holtzman;Charles A Gersbach - Annual review of genomics and human genetics (2018)
  3. The pivotal regulatory landscape of RNA modifications. - Sheng Li;Christopher E Mason - Annual review of genomics and human genetics (2014)
  4. Dynamic RNA Modifications in Gene Expression Regulation. - Ian A Roundtree;Molly E Evans;Tao Pan;Chuan He - Cell (2017)
  5. Regulation of Gene Expression by N6-methyladenosine in Cancer. - Jun Liu;Bryan T Harada;Chuan He - Trends in cell biology (2019)
  6. RNA modifications regulating cell fate in cancer. - Sylvain Delaunay;Michaela Frye - Nature cell biology (2019)
  7. [On the coloration of the caterpillar of Hestina japonica at the beginning of hibernation. II. Pigments of caterpillars of Hestina japonica and Sasakia charonda]. - M Osanai - Hoppe-Seyler's Zeitschrift fur physiologische Chemie (1966)
  8. Nuclear sensing of viral DNA, epigenetic regulation of herpes simplex virus infection, and innate immunity. - David M Knipe - Virology (2015)
  9. Viral gene products actively promote latent infection by epigenetic silencing mechanisms. - David M Knipe;Priya Raja;Jennifer Lee - Current opinion in virology (2017)
  10. Viral DNA Sensors IFI16 and Cyclic GMP-AMP Synthase Possess Distinct Functions in Regulating Viral Gene Expression, Immune Defenses, and Apoptotic Responses during Herpesvirus Infection. - Benjamin A Diner;Krystal K Lum;Jared E Toettcher;Ileana M Cristea - mBio (2016)

引用本文的文献 ​

  1. A SARS-CoV-2 host infection model network based on genomic human Transcription Factors (TFs) depletion. - Massimiliano Chetta;Alessandra Rosati;Liberato Marzullo;Marina Tarsitano;Nenad Bukvic - Heliyon (2020)
  2. Formation of HERV-K and HERV-Fc1 Envelope Family Members is Suppressed on Transcriptional and Translational Level. - Victoria Gröger;Lisa Wieland;Marcel Naumann;Ann-Christin Meinecke;Beate Meinhardt;Steffen Rossner;Christian Ihling;Alexander Emmer;Martin S Staege;Holger Cynis - International journal of molecular sciences (2020)
  3. Epigenetic modification mechanisms involved in keloid: current status and prospect. - Wenchang Lv;Yuping Ren;Kai Hou;Weijie Hu;Yi Yi;Mingchen Xiong;Min Wu;Yiping Wu;Qi Zhang - Clinical epigenetics (2020)
  4. In Silico Analysis of Possible Interaction between Host Genomic Transcription Factors (TFs) and Zika Virus (ZikaSPH2015) Strain with Combinatorial Gene Regulation; Virus Versus Host-The Game Reloaded. - Massimiliano Chetta;Marina Tarsitano;Laura Vicari;Annalisa Saracino;Nenad Bukvic - Pathogens (Basel, Switzerland) (2021)
  5. Aberrant Splicing Events and Epigenetics in Viral Oncogenomics: Current Therapeutic Strategies. - Flavia Zita Francies;Zodwa Dlamini - Cells (2021)
  6. Nonsegmented Negative-Sense RNA Viruses Utilize N6-Methyladenosine (m6A) as a Common Strategy To Evade Host Innate Immunity. - Mijia Lu;Miaoge Xue;Hai-Tao Wang;Elizabeth L Kairis;Sadeem Ahmad;Jiangbo Wei;Zijie Zhang;Qinzhe Liu;Yuexiu Zhang;Youling Gao;Dominique Garcin;Mark E Peeples;Amit Sharma;Sun Hur;Chuan He;Jianrong Li - Journal of virology (2021)
  7. COVID-19: A methyl-group assault? - Andrew McCaddon;Björn Regland - Medical hypotheses (2021)
  8. Tax Induces the Recruitment of NF-κB to Unintegrated HIV-1 DNA To Rescue Viral Gene Expression and Replication. - Ishak D Irwan;Bryan R Cullen - Journal of virology (2021)
  9. Transcriptome-wide N6-methyladenosine modification profiling of long non-coding RNAs during replication of Marek's disease virus in vitro. - Aijun Sun;Xiaojing Zhu;Ying Liu;Rui Wang;Shuaikang Yang;Man Teng;Luping Zheng;Jun Luo;Gaiping Zhang;Guoqing Zhuang - BMC genomics (2021)
  10. Comprehensive profiling analysis of the N6-methyladenosine-modified circular RNA transcriptome in cultured cells infected with Marek's disease virus. - Aijun Sun;Rui Wang;Shuaikang Yang;Xiaojing Zhu;Ying Liu;Man Teng;Luping Zheng;Jun Luo;Gaiping Zhang;Guoqing Zhuang - Scientific reports (2021)

... (83 更多 篇文献)

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