Ruden Douglas M
Department of Obstetrics and Gynecology, C. S. Mott Center for Human Growth and Development, Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Genes (Basel). 2025 Aug 12;16(8):951. doi: 10.3390/genes16080951.
Messenger RNA (mRNA) modifications regulate key steps in gene expression, including splicing, translation, and stability. Despite over 300 known RNA modifications, the relatively small subset occurring in mRNA remains understudied compared with tRNA and rRNA. This review aims to systematically evaluate 15 known naturally occurring mRNA-specific modifications, rank them by publication frequency, and highlight emerging frontiers in epitranscriptomics, including discovering new naturally occurring mRNA modifications and environmental RNA (eRNA) epitranscriptomics. We conducted a structured literature review of PubMed-indexed publications to rank mRNA modifications by citation prevalence. Key modifications such as mA, mC, Ψ, and mA were analyzed in terms of enzymatic machinery ("writers," "erasers," and "readers"), molecular functions, and physiological relevance. We also reviewed technological advances, with a focus on nanopore sequencing for detection of RNA modifications in native and environmental contexts. The modification mA was identified as the most studied mRNA modification, followed by Ψ, mC, and A-to-I editing (inosine). These modifications influence diverse mRNA processes, including translation efficiency, localization, and immune evasion. Cap-specific modifications such as Cap0, Cap1, and Cap2 were also described, highlighting their role in transcript stability and innate immune regulation. Advances in nanopore sequencing have enabled direct detection of RNA modifications and offer promise for eRNA (environmental RNA) surveys. The potential for nanopore sequencing of many other of the 335 known RNA modifications in the MODOMICS database using existing nanopore technologies is also discussed. mRNA modifications represent a critical, yet incompletely mapped, layer of gene regulation. Continued research-especially using nanopore and machine learning technologies-will help uncover their full biological significance. Exploration of eRNA and identifying new mRNA modifications will redefine our understanding of RNA biology.
信使核糖核酸（mRNA）修饰可调控基因表达的关键步骤，包括剪接、翻译和稳定性。尽管已知的RNA修饰有300多种，但与转运RNA（tRNA）和核糖体RNA（rRNA）相比，mRNA中发生的相对较小的子集仍未得到充分研究。本综述旨在系统评估15种已知的天然存在的mRNA特异性修饰，按发表频率对它们进行排名，并突出表观转录组学的新兴前沿领域，包括发现新的天然存在的mRNA修饰和环境RNA（eRNA）表观转录组学。我们对PubMed索引的出版物进行了结构化文献综述，以按引用流行度对mRNA修饰进行排名。对诸如N6-甲基腺嘌呤（mA）、5-甲基胞嘧啶（mC）、假尿苷（Ψ）和肌苷（A-to-I编辑）等关键修饰，从酶机制（“写入器”“擦除器”和“读取器”）、分子功能和生理相关性方面进行了分析。我们还回顾了技术进展，重点是用于在天然和环境背景下检测RNA修饰的纳米孔测序。修饰mA被确定为研究最多的mRNA修饰，其次是Ψ、mC和A-to-I编辑（肌苷）。这些修饰影响多种mRNA过程，包括翻译效率、定位和免疫逃逸。还描述了帽特异性修饰，如Cap0、Cap1和Cap2，突出了它们在转录本稳定性和先天免疫调节中的作用。纳米孔测序的进展使得能够直接检测RNA修饰，并为eRNA（环境RNA）调查带来希望。还讨论了使用现有纳米孔技术对MODOMICS数据库中335种已知RNA修饰中的许多其他修饰进行纳米孔测序的潜力。mRNA修饰代表了基因调控中关键但尚未完全绘制的一层。持续的研究——特别是使用纳米孔和机器学习技术——将有助于揭示它们的全部生物学意义。对eRNA的探索和识别新的mRNA修饰将重新定义我们对RNA生物学的理解。
