Detection, Clinical Application, and Manipulation of RNA Modifications

With increasing research interest, more than 170 types of chemical modifications of RNA have been characterized. The epigenetic modifications of RNA do not alter the primary sequence of RNA but modulate the gene activity. Increasing numbers of regulatory functions of these RNA modifications, particularly in controlling mRNA fate and gene expression, are being discovered. To gain a deeper understanding of the biological significance and clinical prospects of RNA modifications, the development of innovative labeling and detection methodologies is of great importance. Owing to the dynamic features of RNA modifications and the fact that only a portion of genes are modified, detection methods should accurately reveal the precise distribution and modification level of RNA modifications. In general, detection methodologies identify specific RNA modifications in two ways: (1) enriching modification-containing RNAs; and (2) altering the Watson-Crick base pairing pattern to produce truncation or mutation signatures. Additionally, it is important to develop flexible and accurate manipulation tools that enable the installation or removal of RNA modifications at specific positions to investigate the biological functions of a single site. With the development of detection and manipulation methods, the scientific understanding of the biological functions of RNA modifications has increased, paving the way for applications of RNA modifications in disease diagnosis and treatments.In this Account, we provide a brief summary of recent efforts to develop methodologies for detecting RNA modifications. Through the evolution of these detection techniques, our team has uncovered the potential biological roles of RNA modifications in diseases such as diabetic cardiovascular complications, viral infections, and hematologic malignancies. We mainly summarize the recently developed strategies for manipulating RNA modifications. The advent of these programmable editing tools allows for the precise installation or removal of RNA modifications at specific positions. As a result, the biological functions of RNA modifications at these specific loci could be identified, further advancing our knowledge in this field.With this Account, we anticipate providing chemical and biological researchers with comprehensive strategies to discover the underlying mechanisms of RNA modification-mediated biological processes. Although the field of RNA modifications has undergone rapid progress in recent years, our understanding of most of these RNA modifications remains incomplete. We hope to inspire efforts to expand the toolbox for investigating RNA modifications and promote translational research on epigenetics in clinical diagnosis and treatment.