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Post-transcriptional gene regulation by mRNA modifications.
Literature Information
| DOI | 10.1038/nrm.2016.132 |
|---|---|
| PMID | 27808276 |
| Journal | Nature reviews. Molecular cell biology |
| Impact Factor | 90.2 |
| JCR Quartile | Q1 |
| Publication Year | 2017 |
| Times Cited | 1290 |
| Keywords | mRNA modifications, post-transcriptional gene regulation, N6-methyladenosine |
| Literature Type | Journal Article, Review |
| ISSN | 1471-0072 |
| Pages | 31-42 |
| Issue | 18(1) |
| Authors | Boxuan Simen Zhao, Ian A Roundtree, Chuan He |
TL;DR
The discovery of reversible mRNA methylation, particularly N6-methyladenosine (m6A), has revealed a significant mechanism of post-transcriptional gene regulation in eukaryotes, enhancing mRNA metabolism and translation. This modification influences mRNA processing, translation, and decay during critical biological processes such as cell differentiation and stress responses, highlighting the importance of the epitranscriptome in regulating protein synthesis.
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mRNA modifications · post-transcriptional gene regulation · N6-methyladenosine
Abstract
The recent discovery of reversible mRNA methylation has opened a new realm of post-transcriptional gene regulation in eukaryotes. The identification and functional characterization of proteins that specifically recognize RNA N6-methyladenosine (m6A) unveiled it as a modification that cells utilize to accelerate mRNA metabolism and translation. N6-adenosine methylation directs mRNAs to distinct fates by grouping them for differential processing, translation and decay in processes such as cell differentiation, embryonic development and stress responses. Other mRNA modifications, including N1-methyladenosine (m1A), 5-methylcytosine (m5C) and pseudouridine, together with m6A form the epitranscriptome and collectively code a new layer of information that controls protein synthesis.
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Primary Questions Addressed
- What are the specific roles of other mRNA modifications like m1A, m5C, and pseudouridine in post-transcriptional gene regulation?
- How do reversible mRNA methylation processes impact cellular responses to environmental stress?
- In what ways do mRNA modifications influence the fate of mRNAs during embryonic development?
- What experimental techniques are used to study the dynamics of m6A methylation in living cells?
- How might the epitranscriptome be targeted for therapeutic interventions in diseases related to gene regulation?
Key Findings
Research Background and Purpose
The review article discusses the emerging field of post-transcriptional gene regulation through mRNA modifications, particularly focusing on N6-methyladenosine (m6A). This modification is significant as it plays a crucial role in various biological processes, including mRNA metabolism, translation, and decay. The authors aim to summarize recent findings on m6A and other mRNA modifications, elucidating their mechanisms and implications in cellular functions and disease.
Main Methods/Materials/Experimental Design
The review synthesizes findings from various studies that utilize advanced techniques such as:
- Immunoprecipitation with m6A-specific antibodies followed by high-throughput sequencing to map m6A sites across the transcriptome.
- In vitro enzymatic assays to identify methyltransferases (writers) and demethylases (erasers) involved in m6A modification.
- Functional assays to determine the biological roles of m6A reader proteins in mRNA metabolism.
The following flowchart illustrates the key components and processes involved in m6A regulation:
Key Results and Findings
- Prevalence of m6A: m6A is the most abundant internal modification in eukaryotic mRNA, found in various organisms including plants, animals, and viruses.
- Functional Implications: m6A affects nearly all stages of mRNA metabolism:
- Processing: Enhances splicing and export of mRNA.
- Translation: Promotes translation initiation through reader proteins like YTHDF1.
- Decay: Marks mRNA for degradation via YTHDF2, linking m6A to mRNA stability.
- Biological Roles: m6A is involved in critical processes such as cell differentiation, stress responses, and circadian rhythm maintenance.
Main Conclusions/Significance/Innovation
The review highlights the significance of m6A as a dynamic and reversible modification that serves as a regulatory mechanism for gene expression. It proposes that m6A not only influences mRNA metabolism but also acts as a molecular marker that groups transcripts for coordinated processing, thereby facilitating rapid responses to developmental cues and environmental stresses. The concept of the "epitranscriptome" is introduced, emphasizing the additional layer of regulation provided by mRNA modifications.
Research Limitations and Future Directions
- Limitations: The current understanding of m6A dynamics and its interplay with other RNA modifications is still limited. Many questions remain regarding the precise mechanisms by which m6A writers, erasers, and readers are regulated.
- Future Directions: Further research is needed to explore:
- The interactions between m6A and other post-transcriptional modifications.
- The potential roles of m6A in various diseases, including cancer and metabolic disorders.
- The development of more precise mapping techniques for mRNA modifications to enhance our understanding of their functional roles in gene regulation.
Summary Table of m6A Regulators
| Protein | Functional Classification | Biological Functions |
|---|---|---|
| METTL3 | Methyltransferase | Installs m6A; promotes translation |
| METTL14 | Methyltransferase | Key component for m6A installation |
| WTAP | Regulatory subunit | Facilitates m6A installation |
| FTO | Demethylase | mRNA splicing, translation |
| ALKBH5 | Demethylase | mRNA nuclear processing, export |
| YTHDF1 | Reader | Translation initiation |
| YTHDF2 | Reader | mRNA decay |
This structured overview captures the essence of the reviewed literature, highlighting the intricate roles of mRNA modifications in gene regulation and their broader implications in biology and medicine.
References
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- High-resolution N(6) -methyladenosine (m(6) A) map using photo-crosslinking-assisted m(6) A sequencing. - Kai Chen;Zhike Lu;Xiao Wang;Ye Fu;Guan-Zheng Luo;Nian Liu;Dali Han;Dan Dominissini;Qing Dai;Tao Pan;Chuan He - Angewandte Chemie (International ed. in English) (2015)
- FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. - Xu Zhao;Ying Yang;Bao-Fa Sun;Yue Shi;Xin Yang;Wen Xiao;Ya-Juan Hao;Xiao-Li Ping;Yu-Sheng Chen;Wen-Jia Wang;Kang-Xuan Jin;Xing Wang;Chun-Min Huang;Yu Fu;Xiao-Meng Ge;Shu-Hui Song;Hyun Seok Jeong;Hiroyuki Yanagisawa;Yamei Niu;Gui-Fang Jia;Wei Wu;Wei-Min Tong;Akimitsu Okamoto;Chuan He;Jannie M Rendtlew Danielsen;Xiu-Jie Wang;Yun-Gui Yang - Cell research (2014)
- N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. - Xiao Wang;Boxuan Simen Zhao;Ian A Roundtree;Zhike Lu;Dali Han;Honghui Ma;Xiaocheng Weng;Kai Chen;Hailing Shi;Chuan He - Cell (2015)
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Literatures Citing This Work
- Reversible RNA modifications in meiosis and pluripotency. - Arne Klungland;John Arne Dahl;Gareth Greggains;Peter Fedorcsak;Adam Filipczyk - Nature methods (2016)
- Pseudouridine and N6-methyladenosine modifications weaken PUF protein/RNA interactions. - Pavanapuresan P Vaidyanathan;Ishraq AlSadhan;Dawn K Merriman;Hashim M Al-Hashimi;Daniel Herschlag - RNA (New York, N.Y.) (2017)
- SR Proteins: Binders, Regulators, and Connectors of RNA. - Sunjoo Jeong - Molecules and cells (2017)
- NSUN2-Mediated m5C Methylation and METTL3/METTL14-Mediated m6A Methylation Cooperatively Enhance p21 Translation. - Qiu Li;Xiu Li;Hao Tang;Bin Jiang;Yali Dou;Myriam Gorospe;Wengong Wang - Journal of cellular biochemistry (2017)
- Antibodies specific for nucleic acid modifications. - Regina Feederle;Aloys Schepers - RNA biology (2017)
- RNA modifications go viral. - Nandan S Gokhale;Stacy M Horner - PLoS pathogens (2017)
- Chemical and Conformational Diversity of Modified Nucleosides Affects tRNA Structure and Function. - Ville Y P Väre;Emily R Eruysal;Amithi Narendran;Kathryn L Sarachan;Paul F Agris - Biomolecules (2017)
- The Epitranscriptome of Noncoding RNAs in Cancer. - Manel Esteller;Pier Paolo Pandolfi - Cancer discovery (2017)
- A fly view on the roles and mechanisms of the m6A mRNA modification and its players. - Tina Lence;Matthias Soller;Jean-Yves Roignant - RNA biology (2017)
- X chromosome inactivation: new players in the initiation of gene silencing. - Ines Pinheiro;Edith Heard - F1000Research (2017)
... (1280 more literatures)
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