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Epigenetic and epitranscriptomic regulation of viral replication. ​

Literature Information ​

DOI10.1038/s41579-020-0382-3
PMID32533130
JournalNature reviews. Microbiology
Impact Factor103.3
JCR QuartileQ1
Publication Year2020
Times Cited93
KeywordsEpigenetics, Epitranscriptomics, Viral Replication
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Review
ISSN1740-1526
Pages559-570
Issue18(10)
AuthorsKevin Tsai, Bryan R Cullen

TL;DR ​

This review explores the dual role of host epigenetic and epitranscriptomic modifications in regulating viral gene expression, highlighting how these processes can both inhibit and facilitate viral replication. The findings suggest that understanding these interactions may provide new avenues for antiviral drug development by targeting chromatin and RNA modifications.

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Epigenetics · Epitranscriptomics · Viral Replication

Abstract ​

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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Primary Questions Addressed ​

  1. How do specific epigenetic modifications on histones impact the replication of different types of viruses?
  2. In what ways do viruses exploit epitranscriptomic modifications to enhance their gene expression during infection?
  3. What are the potential therapeutic strategies targeting epigenetic and epitranscriptomic mechanisms in antiviral drug development?
  4. How do host cells differentiate between beneficial and detrimental epigenetic modifications during viral infections?
  5. What role do non-coding RNAs play in the epigenetic and epitranscriptomic regulation of viral replication?

Key Findings ​

Research Background and Objectives ​

The regulation of gene expression in eukaryotic cells involves both genomic elements and various covalent modifications to chromatin and RNA. This review focuses on the dual roles of epigenetic and epitranscriptomic modifications in regulating viral replication. The authors aim to explore how these modifications affect viral gene expression and how viruses have adapted to manipulate these processes for their advantage.

Main Methods/Materials/Experimental Design ​

The review employs a comprehensive literature analysis to discuss the mechanisms of epigenetic repression and epitranscriptomic modifications in the context of viral infections. Key mechanisms include:

  • Epigenetic Regulation: This involves modifications to histones and DNA, affecting chromatin structure and accessibility.
  • Epitranscriptomic Modifications: These include various RNA modifications that influence mRNA stability, translation, and immune evasion.

Technical Route (Mermaid Code) ​

Mermaid diagram

Key Results and Findings ​

  1. Epigenetic Repression: Viruses like herpesviruses and HBV can be epigenetically silenced by host factors such as PML-NBs and IFI16. These mechanisms inhibit viral gene expression, acting as a form of innate immune response.
  2. Viral Adaptations: Viruses have evolved strategies to counteract epigenetic repression. For example, HSV-1 uses the protein VP16 to recruit demethylases that remove repressive marks from its DNA.
  3. Epitranscriptomic Modifications: RNA modifications such as m6A, m5C, ac4C, and Nm enhance viral replication by increasing mRNA stability and translation while also aiding in evasion of host immune responses.

Main Conclusions/Significance/Innovation ​

The findings underscore the complexity of the interactions between host epigenetic regulation and viral strategies. The ability of viruses to manipulate these processes not only aids in their replication but also highlights potential therapeutic targets for antiviral drug development. Targeting epigenetic and epitranscriptomic pathways could lead to innovative strategies for treating viral infections.

Research Limitations and Future Directions ​

The review acknowledges gaps in understanding how host cells distinguish between viral and host DNA, particularly regarding unintegrated HIV-1 DNA. Future research should focus on:

  • Elucidating the mechanisms of epitranscriptomic modification selection.
  • Identifying readers for various RNA modifications.
  • Exploring the therapeutic potential of targeting these pathways in antiviral strategies.

Summary Table of Key Epitranscriptomic Modifications ​

ModificationWriterEffect on Viral Replication
m6AMETTL3Increases RNA expression, evades RIG-I
m5CNSUN2Enhances mRNA translation
ac4CNAT10Increases RNA stability
NmFTSJ3Avoids MDA5 detection

This structured overview provides a comprehensive understanding of the roles of epigenetic and epitranscriptomic modifications in viral replication, emphasizing the dynamic interplay between host defenses and viral evasion strategies.

References ​

  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)

Literatures Citing This Work ​

  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 more literatures)

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