The role of N 6 -methyladenosine (m 6 A) modification in the regulation of circRNAs

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Abstract

N ⁶-methyladenosine (m ⁶A), the most abundant modification in eukaryotic cells, regulates RNA transcription, processing, splicing, degradation, and translation. Circular RNA (circRNA) is a class of covalently closed RNA molecules characterized by universality, diversity, stability and conservatism of evolution. Accumulating evidence shows that both m ⁶A modification and circRNAs participate in the pathogenesis of multiple diseases, such as cancers, neurological diseases, autoimmune diseases, and infertility. Recently, m ⁶A modification has been identified for its enrichment and vital biological functions in regulating circRNAs. In this review, we summarize the role of m ⁶A modification in the regulation and function of circRNAs. Moreover, we discuss the potential applications and possible future directions in the field.

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Most cited references 43

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Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses

William W. Du, Weining Yang, Yu Chen … (2017)

Circular RNAs are a subclass of non-coding RNAs detected within mammalian cells. This study was designed to test the roles of a circular RNA circ-Foxo3 in senescence using in vitro and in vivo approaches.

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m 6 A enhances the phase separation potential of mRNA

Ryan Ries, Sara Zaccara, Pierre Klein … (2019)

N 6-methyladenosine (m6A) is the most prevalent modified nucleotide in mRNA 1,2 , with ~25% of mRNAs containing at least one m6A. Methylation of mRNA to form m6A is required for diverse cellular and physiological processes 3 . Although the presence of m6A in an mRNA can affect its fate in different ways, it is unclear how m6A directs this process and why the effects of m6A can vary in different cellular contexts. Here we show that the cytosolic m6A-binding proteins, YTHDF1–3, undergo liquid-liquid phase separation (LLPS) in vitro and in cells. This LLPS is markedly enhanced by mRNAs that contain multiple, but not single, m6A residues. Polymethylated mRNAs act as a multivalent scaffold for binding YTHDF proteins, juxtaposing their low-complexity domains, leading to phase separation. The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated compartments, such as P-bodies, stress granules, or neuronal RNA granules. m6A-mRNA is subject to compartment-specific regulation, including reduced mRNA stability and translation. These studies reveal that the number and distribution of m6A sites in cellular mRNAs can regulate and influence the composition of the phase-separated transcriptome. Additionally, these findings indicate that the cellular properties of m6A-modified mRNAs are governed by liquid-liquid phase separation principles.

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Transcriptome-wide discovery of circular RNAs in Archaea

Miri Danan-Gotthold, Schraga Schwartz, Sarit Edelheit … (2011)

Circular RNA forms had been described in all domains of life. Such RNAs were shown to have diverse biological functions, including roles in the life cycle of viral and viroid genomes, and in maturation of permuted tRNA genes. Despite their potentially important biological roles, discovery of circular RNAs has so far been mostly serendipitous. We have developed circRNA-seq, a combined experimental/computational approach that enriches for circular RNAs and allows profiling their prevalence in a whole-genome, unbiased manner. Application of this approach to the archaeon Sulfolobus solfataricus P2 revealed multiple circular transcripts, a subset of which was further validated independently. The identified circular RNAs included expected forms, such as excised tRNA introns and rRNA processing intermediates, but were also enriched with non-coding RNAs, including C/D box RNAs and RNase P, as well as circular RNAs of unknown function. Many of the identified circles were conserved in Sulfolobus acidocaldarius, further supporting their functional significance. Our results suggest that circular RNAs, and particularly circular non-coding RNAs, are more prevalent in archaea than previously recognized, and might have yet unidentified biological roles. Our study establishes a specific and sensitive approach for identification of circular RNAs using RNA-seq, and can readily be applied to other organisms.

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Author and article information

Contributors

Detao Yin: detaoyin@zzu.edu.cn

Jinbo Liu: 1999liujb@163.com

Zhenqiang Sun:

ORCID: http://orcid.org/0000-0001-5926-2716

zqsun82@csu.edu.cn

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 10 June 2020

Publication date PMC-release: 10 June 2020

Publication date Collection: 2020

Volume: 19

Electronic Location Identifier: 105

Affiliations

[1 ]GRID grid.412633.1, Department of Colorectal Surgery, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, 450052 Henan China

[2 ]GRID grid.460080.a, Department of Colorectal Surgery, , Zhengzhou Central Hospital, Zhengzhou University, ; Zhengzhou, 450007 Henan China

[3 ]GRID grid.412633.1, Department of Thyroid Surgery, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, 450052 Henan China

[4 ]GRID grid.207374.5, ISNI 0000 0001 2189 3846, Academy of Medical Sciences, , Zhengzhou University, ; Zhengzhou, 450052 Henan China

[5 ]GRID grid.207374.5, ISNI 0000 0001 2189 3846, School of Life Sciences, , Zhengzhou University, ; Zhengzhou, 450001 Henan China

[6 ]GRID grid.207374.5, ISNI 0000 0001 2189 3846, School of Basic Medical Sciences, , Zhengzhou University, ; Zhengzhou, 450002 Henan China

Author information

Zhenqiang Sun http://orcid.org/0000-0001-5926-2716

Article

Publisher ID: 1224

DOI: 10.1186/s12943-020-01224-3

PMC ID: 7285594

PubMed ID: 32522202

SO-VID: 30f388ac-ebb3-49b3-bf8d-767088daad98

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 5 February 2020

Date accepted : 28 May 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81972663

Award ID: 81560385