RNA modifications in gene regulation: Functions and pathways

RNA is frequently chemically modified, with over 170 types of chemical modifications identified to date in cellular RNAs. These modifications, along with their effector proteins, constitute new layers of gene expression regulation by controlling either the fate of modified RNAs at nearly every stage of their life cycle or local transcription through modulating the nearby chromatin state and transcriptional complexes. This is especially evident in dynamic biological contexts such as cellular state transitions, signaling, immune responses, and stress adaptation. In this review, we discuss recent breakthroughs and promising avenues for future exploration. Particular attention is given to the functional significance of mRNA modifications, the emerging roles of modifications on chromatin-associated regulatory RNAs in chromatin and transcriptional regulation, and mechanistic insights that will guide future scientific interrogation of RNA modifications in gene expression regulation. We also highlight how these fundamental understandings are beginning to catalyze the development of novel therapeutic strategies.