MicroRNA chemical modifications in post-transcriptional gene silencing and human diseases

MicroRNAs (miRNAs) are small, non-coding RNAs that influence various cellular activities through post-transcriptional gene silencing. Recent research has shown that miRNA modifications, including N6-methyladenosine (m6A), 5-methylcytidine (m5C), 2'-O-methylation (Nm), N7-methylguanosine (m7G), pseudouridylation (Ψ), phosphorylation, RNA editing (adenosine to inosine [A to I]), acetylation, and oxidation, play crucial roles in fine-tuning miRNA expression and function. This review examines the impact of nucleotide modifications on miRNA biogenesis, particularly their role in regulating RNA interactions with the Drosha-DiGeorge syndrome critical region 8 (DGCR8) and Dicer complexes, thereby influencing primary miRNA (pri-miRNA) processing, pre-miRNA export, and miRNA maturation. It also examines whether these modifications assist miRNA recognition by RNA-binding proteins (RBPs) in controlling miRNA processing and stability, as well as their impact on miRNA strand selection, target recognition, and the recruitment of regulatory proteins to the miRNA-induced silencing complex (miRISC), which facilitates the silencing of miRNA-targeted messenger RNAs (mRNAs). Additionally, the review discusses the role of miRNA modifications in various human diseases and considers how advanced sequencing technologies and chemical biology approaches enable detailed mapping of these modifications. Furthermore, it provides new insights into the challenges of understanding the dynamic nature of miRNA modifications and their context-dependent effects. It also highlights future directions, including innovative detection methods and epigenetic crosstalk with potential therapeutic applications in human diseases.