Regulatory elements on chromatin-associated RNA 15 years beyond RNA epigenetics

Chemical modifications on RNA represent an additional regulatory layer of gene expression analogous to epigenetic marks on DNA and histones. Over the past decade, the fundamental mechanisms of N⁶-methyladenosine and other mRNA modifications have been extensively characterized, establishing their roles in nearly all aspects of RNA metabolism with broad implications for physiological and pathological processes. These advances lay the groundwork for future therapeutic approaches targeting mRNA modification pathways. By contrast, emerging evidence indicates that RNA methylation on chromatin-associated RNAs (caRNAs) intersects with chromatin regulators to modulate chromatin state and transcription, adding a new dimension to epigenetic regulation with biological significance. Here we summarize established principles of post-transcriptional RNA modifications and their therapeutic potential, highlight the rapidly developing chromatin-related functions of RNA modifications as regulatory elements on caRNAs and discuss future directions that emphasize the need to investigate additional regulatory elements on these RNAs in shaping gene expression programs.