Chemical Modifications to RNA: A New Layer of Gene Expression Regulation

The first chemical modification to RNA was discovered nearly 60 years ago; to date, more than 100 chemically distinct modifications have been identified in cellular RNA. With the recent development of novel chemical and/or biochemical methods, dynamic modifications to RNA have been identified in the transcriptome, including N⁶-methyladenosine (m⁶A), inosine (I), 5-methylcytosine (m⁵C), pseudouridine (Ψ), 5-hydroxymethylcytosine (hm⁵C), and N¹-methyladenosine (m¹A). Collectively, the multitude of RNA modifications are termed epitranscriptome, leading to the emerging field of epitranscriptomics. In this review, we primarily focus on recently reported chemical modifications to mRNA; we discuss their chemical properties, biological functions, and mechanisms with an emphasis on their high-throughput detection methods. We also envision that future tools, particularly novel chemical biology methods, could further facilitate and enable studies in the field of epitranscriptomics.