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Dynamic RNA Modifications in Gene Expression Regulation. ​

Literature Information ​

DOI10.1016/j.cell.2017.05.045
PMID28622506
JournalCell
Impact Factor42.5
JCR QuartileQ1
Publication Year2017
Times Cited1801
KeywordsRNA modification, gene expression regulation, m6A modification
Literature TypeJournal Article, Review
ISSN0092-8674
Pages1187-1200
Issue169(7)
AuthorsIan A Roundtree, Molly E Evans, Tao Pan, Chuan He

TL;DR ​

This research highlights the significance of various RNA chemical modifications, particularly N6-methyladenosine (m6A), in regulating mRNA metabolism and function, emphasizing their roles in the mRNA life cycle and diverse cellular processes. The findings suggest that these dynamic modifications introduce a new layer of regulatory complexity in both coding and noncoding RNAs, enhancing our understanding of genetic information control.

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RNA modification · gene expression regulation · m6A modification

Abstract ​

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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Primary Questions Addressed ​

  1. How do different types of RNA modifications influence the stability and translation efficiency of mRNA?
  2. What specific roles do proteins that recognize and remove m6A modifications play in cellular processes?
  3. How might the dynamic nature of RNA modifications impact our understanding of gene expression in various diseases?
  4. In what ways do modifications on noncoding RNAs, such as tRNAs and rRNAs, affect their functionality and interaction with other cellular components?
  5. What experimental techniques are currently being used to study the effects of RNA modifications on gene regulation and cellular behavior?

Key Findings ​

Research Background and Purpose ​

The review discusses the dynamic RNA modifications that regulate gene expression, emphasizing the growing understanding of how these modifications influence various biological processes. The primary focus is on N6-methyladenosine (m6A), the most prevalent internal modification in mRNA, and its roles in mRNA metabolism, stability, and cellular functions.

Main Methods/Materials/Experimental Design ​

The review employs a comprehensive approach, synthesizing existing literature and recent advancements in RNA modification research. Key methodologies include:

  • Detection Techniques: High-throughput sequencing and analytical chemistry methods to identify and quantify RNA modifications.
  • Functional Studies: Investigations into the roles of specific RNA modifications (e.g., m6A, m1A, m5C) in regulating gene expression, stability, and translation.
  • Biochemical Analysis: Characterization of enzymes responsible for RNA modifications and demodifications, such as methyltransferases and demethylases.
Mermaid diagram

Key Results and Findings ​

  • m6A Modification: Found to be critical for various aspects of the mRNA life cycle, including processing, transport, translation, and degradation.
  • Dynamic Nature: The review highlights that RNA modifications are not static; they can be added or removed in response to cellular conditions, indicating a layer of regulation beyond genetic sequence.
  • Functional Impact: Modifications such as m6A, m1A, and m5C influence RNA-protein interactions, secondary structures, and the overall stability of RNA molecules.

Main Conclusions/Significance/Innovativeness ​

The findings underscore the importance of RNA modifications in gene regulation and cellular function. The review suggests that:

  • RNA modifications, particularly m6A, provide a dynamic regulatory mechanism that allows cells to respond rapidly to environmental changes.
  • Understanding these modifications opens new avenues for research into their roles in diseases, including cancer and neurological disorders, highlighting their potential as therapeutic targets.

Research Limitations and Future Directions ​

  • Methodological Challenges: The review notes that while detection techniques have advanced, there is still a need for improved methods to quantify RNA modifications with high sensitivity and resolution.
  • Biological Complexity: The interactions and regulatory mechanisms involving RNA modifications are complex and not fully understood, necessitating further investigation.
  • Future Research: Future studies should focus on elucidating the precise roles of various RNA modifications in different cellular contexts and their implications in health and disease.

Summary Table of Key Modifications ​

ModificationDescriptionKey Functions
m6AMost abundant internal mRNA modificationRegulates mRNA stability, translation, and decay
m1AMethylation at the N1 position of adenosineAffects RNA structure and translation efficiency
m5CMethylation at the 5 position of cytosineImpacts mRNA export and stability
JIsomerization of uridineInfluences RNA secondary structure and translation
20-OMeMethylation of ribose 2' hydroxylEnhances RNA stability and structural integrity

This structured overview encapsulates the essential findings and implications of the review on RNA modifications, highlighting their significance in gene expression regulation and potential roles in disease mechanisms.

References ​

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  8. Structural Basis for the Discriminative Recognition of N6-Methyladenosine RNA by the Human YT521-B Homology Domain Family of Proteins. - Chao Xu;Ke Liu;Hazem Ahmed;Peter Loppnau;Matthieu Schapira;Jinrong Min - The Journal of biological chemistry (2015)
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Literatures Citing This Work ​

  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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