Over 170 RNA modifications have been discovered thus far, with widespread distribution on non-coding RNAs. Advancements in detection technologies have unveiled multiple chemical modifications on mRNAs of higher eukaryotes, leading to the emergence of a novel research field called epigenomics that has revolutionized our understanding of post-transcriptional regulation and propelled the advancement of RNA biology.
In recent years, mRNA-based therapy, which is founded on the induction of transient translation with the cell's ribosomes of fully functional proteins without integration into the host genome has become a potential drug for cancer immunotherapy and prophylactic vaccines. Compared with conventional gene therapy and protein substitution strategies, in vitro synthetic mRNA has several advantages. However, the instability and immunogenicity of mRNA, which are caused by the lack of a cap structure at the 5' end and a long sequence of polyadenylate residues at the 3' end, have hampered the development of mRNA therapy for many years. Later on with the technical advancements, synthetically manufactured mRNA can be modified to include these components, and thereby improve the stability of synthetic mRNAs, minimize immunogenicity, and boost translation efficiency.
On June 27, 2023, Chengqi Yi's team at Peking University published a comprehensive review paper titled "Regulation and Functions of Non-m6A mRNA Modifications" in Nature Reviews Molecular Cell Biology. This paper provides an in-depth understanding of RNA biology and advances the knowledge of epistatic transcriptomics.
Among the various chemical modifications, N6-methyladenine (m6A) is the most abundant modification found in eukaryotic mRNAs and has been extensively studied. Over the past decade, the regulatory proteins associated with m6A modifications, including methyltransferases, binding proteins, and demethylases, have been discovered. Additionally, various whole transcriptome sequencing technologies have been developed, enabling the exploration of the biological functions and regulatory mechanisms of m6A modifications.
In addition to m6A, mRNA can undergo other chemical modifications, such as pseudouridine modification (Ψ), N1-methyladenine (m1A), 5-methylcytosine (m5C), N6,2'-O-dimethyladenine (m6Am), hypoxanthine (Inosine), N4-acetylcytosine (ac4C), 2'-O-methyl nucleoside (Nm), and internal N7-methylguanine (m7G).
Similar to m6A modifications, advancements in sequencing methods and the identification of regulatory effector proteins have stimulated research on the biosynthesis, distribution characteristics, molecular functions, and regulatory mechanisms of these other modifications. Numerous studies have demonstrated that these modifications on mRNAs play pivotal regulatory roles in important physiological processes and human diseases.
However, the majority of reviews on transcriptome modifications predominantly focus on m6A modifications, making a comprehensive overview of other types of chemical modifications on mRNAs essential. This review specifically delves into the regulatory mechanisms and biological functions of modifications other than m6A on mRNAs. It provides detailed insights into known effector proteins, detection techniques, and distribution characteristics of these modifications. Additionally, it summarizes their roles in mRNA metabolism and their regulatory functions under physiological and pathological conditions. Furthermore, the review explores potential future research techniques and applications of modifications other than m6A on mRNAs.