The Role of 2′‐O‐Methylation in Epitranscriptomic Regulation: Gene Expression, Physiological Functions and Applications

ABSTRACT Since the discovery of pseudouridine in the 1950s, the field of epitranscriptomics has expanded substantially, with over 330 RNA modifications now documented in the MODOMICS database. Among these, 2′‐O‐ribose methylation (2′‐O‐Me) is a prevalent modification characterized by the addition of a methyl group to the 2′‐hydroxyl position of the ribose sugar, irrespective of the nucleotide bases. Initially detected in ribosomal RNA (rRNA), transfer RNA (tRNA), and messenger RNA (mRNA) in the 1970s, the methyltransferases responsible for 2′‐O‐Me were subsequently identified starting in the 1980s. Advancements in transcriptome‐wide mapping techniques have since enabled precise identification of 2′‐O‐Me sites across various RNA species. Functional studies using knockdown or knockout models of specific 2′‐O‐Me methyltransferases have further elucidated their roles in different physiological processes. Notably, dysregulation of 2′‐O‐Me has been implicated in human diseases, including cancers and neurological disorders, underscoring its significance in controlling cellular homeostasis. This review covers the catalytic mechanisms and molecular functions of 2′‐O‐Me in different RNA species, discusses its physiological importance, and highlights the methods for transcriptome‐wide mapping of this modification.