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M6a Modification in RNA: Biogenesis, Functions and Roles in Gliomas

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Zhang et al. Journal of Experimental & Clinical Cancer Research (2020) 39:192 https://doi.org/10.1186/s13046-020-01706-8 REVIEW Open Access m6A modification in RNA: biogenesis, functions and roles in gliomas Yuhao Zhang1†, Xiuchao Geng2†, Qiang Li3, Jianglong Xu1, Yanli Tan4, Menglin Xiao1, Jia Song5, Fulin Liu6*, Chuan Fang1* and Hong Wang1,2,7* Abstract The chemical modification of RNA is a newly discovered epigenetic regulation mechanism in cells and plays a crucial role in a variety of biological processes. N6-methyladenine (m6A) mRNA modification is the most abundant form of posttranscriptional RNA modification in eukaryotes. Through the development of m6A RNA sequencing, the relevant molecular mechanism of m6A modification has gradually been revealed. It has been found that the effect of m6A modification on RNA metabolism involves processing, nuclear export, translation and even decay. As the most common malignant tumour of the central nervous system, gliomas (especially glioblastoma) have a very poor prognosis, and treatment efficacy is not ideal even with the application of high-intensity treatment measures of surgery combined with chemoradiotherapy. Exploring the origin and development mechanisms of tumour cells from the perspective of tumour biogenesis has always been a hotspot in the field of glioma research. Emerging evidence suggests that m6A modification can play a key role in gliomas through a variety of mechanisms, providing more possibilities for early diagnosis and targeted therapy of gliomas. The aim of the present review is to focus on the research progress regarding the association between m6A modification and gliomas. And to provide a theoretical basis according to the currently available literature for further exploring this association. This review may provide new insights for the molecular mechanism, early diagnosis, histologic grading, targeted therapy and prognostic evaluation of gliomas. Keywords: m6A modification, RNA, Central nervous system, Glioma, Glioblastoma, GBM, Tumourigenesis Background degree of mitotic activity. Given the aggressiveness of Gliomas are the most common malignancy in the cen- GBM, surgical resection to resolve all intracranial lesions tral nervous system. Glioblastoma (GBM) has the high- in clinical practice is challenging. Therefore, most est malignancy rate and account for 50% of all brain patients receive radiotherapy and temozolomide (TMZ) tumours. The average survival time of patients with combined with chemotherapy after surgery. Although GBM is only 14.6 months [1]. GBM originate from the treatment intensity is very high, the outcomes are poorly differentiated glial cells and have the characteris- still not satisfactory [2–5]. Therefore, there is an urgent tics of nuclear atypia, cellular polymorphism, and a high need for new treatment strategies or regimens. To improve the efficacy of GBM treatment, it is neces- * Correspondence: [email protected]; [email protected]; sary to understand the occurrence and development of [email protected] GBM and determine the molecular biological character- † Yuhao Zhang and Xiuchao Geng contributed equally to this work. istics of GBM. In recent years, with the in-depth study 6Office of Academic Research, Affiliated Hospital of Hebei University, 071000 Baoding, China of the epigenetics, metabolism, and immunology of 1Department of Neurosurgery, Affiliated Hospital of Hebei University, 071000 GBM, our knowledge of GBM has greatly expanded, Baoding, China which provides new clues for the treatment of GBM. Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This 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. Zhang et al. Journal of Experimental & Clinical Cancer Research (2020) 39:192 Page 2 of 16 Recent studies have found that non-coding RNAs and Approaches of detecting of m6A modification post transcriptional modification of RNAs have become The total amount of m6A in RNA can be probed by sev- the active fields of cancer research. Among them, N6- eral approaches, including two-dimensional thin layer methyladenine (m6A) RNA modification is the import- chromatography, m6A dot-blot and high-performance li- ant research hotspot [6, 7]. More than 60% of all RNA quid chromatography-tandem mass spectrometry (HPLC- modifications are methylated modifications, and m6A is MS/MS) [15, 16]. the most abundant chemical modification in eukaryotic The transcriptome-wide distribution of m6A was un- messenger RNA (mRNA). As a representative of relevant clear before 2012, until methylated RNA immunoprecip- studies, epigenetics found that m6A RNA modification itation followed by high-throughput sequencing (MeRIP- plays important roles in the regulation of cell fate, prolif- seq or m6A-seq) was developed [17, 18]. In this method, eration, and metabolism and the biogenesis of tumours mRNA was fragmented into 100-nt-long oligonucleo- [6–9]. It also opens a new way of thinking for biomedical tides and immunoprecipitated with a specific antibody scientists, whether RNA modification will be another against m6A. Then immunoprecipitated RNAs were sub- important factor to regulate the biological development jected to high-throughput sequencing. Other approaches of neoplastic diseases. for higher resolution, such as photo-crosslinking-assisted In this review, we provide a comprehensive intro- m6A-sequencing (PA-m6A-Seq) and site-specific cleavage duction of the latest research progress on m6A modi- and radioactive-labelling followed by ligation-assisted fication and elucidate the origin of m6A modification, extraction and thin-layer chromatography (SCARLET) its regulation, biological functions and its correlation [19, 20]. Currently, a novel method called m6A indi- with the central nervous system and gliomas. And to vidual nucleotide resolution crosslinking immunopre- discuss the prospect of the possible research direc- cipitation (miCLIP) has marked a major step forward tions. Aiming at providing a theoretical basis accord- in the field, which could detect m6A at precise position ing to the currently available literature for further [21]. Furthermore, with the development of CRISPR-based exploring the association between m6A modification genome engineering, it is currently possible to directly de- and gliomas. tect the effect of altering any m6A modification site in many organisms. As a supplementary approach, it would The molecular mechanisms of m6A modification be valuable for discovering the functions of m6A methyla- Origin of m6A modification tion [22, 23]. With the advent of high-throughput sequencing technol- Current studies have shown that in addition to mRNA, ogy, scientists have identified nearly 170 types of RNA microRNA (miRNA), long noncoding RNAs (lncRNA), modification, also known as “epitranscriptomics” [10]. circular RNA (circRNA), ribosomal RNA (rRNA), trans- Inserting information beyond the information carried by fer RNA (tRNA) and small nucleolar RNAs (snoRNA) their base sequences to gene transcripts, altering the all have m6A modifications and that their regulation in- charge of RNA bases and their matching properties, volves almost all categories of protein-coding genes and differential folding of RNAs, and the formation of a noncoding genes [24, 25]. regulatory protein-RNA interaction recognition element are classical transcriptome modification processes. There- Regulation of m6A modification fore, these modifications are involved in the whole process m6A modification mainly occurs in adenines in the of RNA metabolism, regulating the fine expression pat- RRACH sequence, and its functions are implemented by terns of genes and, ultimately, affecting the biological be- RNA methyltransferases (writers), RNA demethylase haviour of cells [11, 12]. (erasers) and m6A binding protein (readers). We sum- When the m6A modification was first discovered in marized the types of proteins involved in m6A modifica- mRNA, only a few modified sites were mapped in viral tion (Fig. 1). In addition, we offered some explanations and cellular RNAs, but not in the human coding region for some of these important biological functions. or noncoding region [13]. In 2012, Dominissini and col- leagues developed m6A sequencing (m6A-seq) technol- m6A “writer” ogy. They presented the first modification landscape in Methyltransferase like 3 (METTL3) is a key protein with a transcriptome-wide manner using m6A-seq, proved molecular weight of 70 kDa and was the first protein the evolutionary conservation of m6A sites and identi- identified
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