Emerging Roles of RNA Methylation in Development

ConspectusMore than 170 different types of chemical modifications have been identified on diverse types of RNA, collectively known as the epitranscriptome. Among them, N6-methyladenine (m6A), 5-methylcytosine (m5C), N1-methyladenine (m1A), and N7-methylguanosine (m7G) as the ubiquitous post-transcriptional modification are widely involved in regulating the metabolic processes such as RNA degradation, translation, stability, and export, mediating important physiological and pathological processes such as stress regulation, immune response, development, and tumorigenesis. Recently, the regulatory role of RNA modification during developmental processes is getting more attention. Therefore, the development of low-input even single-cell and high-resolution sequencing technologies is crucial for the exploration of the regulatory roles of RNA modifications in these important biological events of trace samples.This account focuses on the roles of RNA modifications in various developmental processes. We describe the distribution characteristics of various RNA modifications, catalytic enzymes, binding proteins, and the development of sequencing technologies. RNA modification is dynamically reversible, which can be catalyzed by methyltransferases and eliminated by demethylases. RNA m6A is the most abundant post-transcriptional modification on eukaryote mRNA, which is mainly concentrated near the stop codon, and involves in RNA metabolism regulation. RNA m5C, another most studied RNA modification, has been identified in a various of organisms and RNA species, mainly enriched in the regions downstream of translation initiation sites and broadly distributes across the whole coding sequence (CDS) in mammalian mRNAs. RNA m1A, with a lower abundance than m6A, is widely distributed in various RNA types, mainly locates in the 5′ untranslated region (5′UTR) of mRNA and regulates translation. RNA m7G, one of the most common RNA modifications in eukaryotes, has been identified at cap regions and internal positions of RNAs and recently gained considerable attention.Thanks to the development of sequencing technology, m6A has been found to regulate the tumorigenic process, including tumor proliferation, invasion, and metastasis by modulating oncogenes and tumor suppressor genes, and affect oocyte maturation and embryonic development through regulating maternal and zygotic genes. m5C related proteins have been identified to participate in embryonic development, plant growth, and neural stem cell differentiation in a m5C dependent manner. m1A also has been revealed to be involved in these developmental processes. m7G dysregulation mainly involves in neurodevelopmental disorders and neurodegenerative diseases.Collectively, we summarized the gradually exhibited roles of RNA methylation during development, and discussed the possibility of RNA modifications as candidate biomarkers and potential therapeutic targets. The technological development is anticipated as the major driving force to expand our knowledge in this field.概要：目前已在各类RNA上鉴定出超过170种不同的化学修饰，这些修饰统称为表观转录组（epitranscriptome）。其中，N6-甲基腺嘌呤（m6A）、5-甲基胞嘧啶（m5C）、N1-甲基腺嘌呤（m1A）以及N7-甲基鸟苷（m7G）作为普遍存在的转录后修饰，广泛参与调控RNA降解、翻译、稳定性与输出等代谢过程，介导应激调控、免疫应答、发育及肿瘤发生等重要生理与病理进程。近年来，RNA修饰在发育过程中的调控作用愈发受到学界关注。因此，开发低起始量甚至单细胞级别的高分辨率测序技术，对于探究RNA修饰在微量样本的这类重要生物学事件中的调控功能至关重要。本综述聚焦于RNA修饰在各类发育过程中的作用，阐述了各类RNA修饰、催化酶、结合蛋白的分布特征，以及测序技术的发展历程。RNA修饰具有动态可逆性：甲基转移酶可催化修饰的添加，而去甲基化酶则可将其清除。m6A是真核生物mRNA上丰度最高的转录后修饰，主要富集于终止密码子附近，参与RNA代谢调控。m5C是另一类研究较为深入的RNA修饰，已在多种生物与RNA物种中被鉴定，主要富集于翻译起始位点下游区域，并广泛分布于哺乳动物mRNA的全编码序列（CDS）中。m1A的丰度低于m6A，广泛分布于各类RNA中，主要定位于mRNA的5'非翻译区（5'UTR）并调控翻译过程。m7G是真核生物中最常见的RNA修饰之一，已在RNA的帽结构区域与内部位点被鉴定，近年来受到广泛关注。得益于测序技术的发展，现已发现m6A可通过调控癌基因与抑癌基因，参与肿瘤增殖、侵袭与转移等肿瘤发生过程；还可通过调控母源基因与合子基因，影响卵母细胞成熟与胚胎发育。研究证实，m5C相关蛋白以m5C依赖的方式参与胚胎发育、植物生长及神经干细胞分化等过程。m1A也被发现参与上述发育过程。m7G的调控异常主要与神经发育障碍及神经退行性疾病相关。综上，本综述总结了RNA甲基化在发育过程中逐渐被揭示的作用，并探讨了RNA修饰作为候选生物标志物与潜在治疗靶点的可能性。未来，技术发展有望成为拓展该领域研究认知的核心驱动力。