Deciphering the regulatory landscape of enhancer RNAs in health and disease

Enhancers are distal cis-regulatory elements that orchestrate spatiotemporal gene expression patterns in response to developmental cues and environmental stimuli. Genetic and epigenetic alterations in enhancers are associated with the initiation and progression of human diseases, including cancers. Over the past few decades, accumulating evidence has revealed that a class of nascent RNA transcripts, known as enhancer RNAs (eRNAs), is broadly transcribed from active enhancers. These eRNA species contribute to complex and dynamic gene regulatory networks under both physiological and pathological conditions through diverse mechanisms. Notably, dysregulated eRNA expression has been reported across various cancer types and is often correlated with patient survival outcomes. Consequently, eRNAs are emerging as promising biomarkers and therapeutic targets for cancer treatment. This review provides a comprehensive summary of the current understanding of eRNAs and their mechanisms of action in gene regulation. We discuss the critical roles of eRNAs in both health and disease and highlight their diagnostic and prognostic value, as well as their therapeutic potential in cancer. Additionally, we review current strategies for targeting RNA transcripts, including eRNAs, and discuss the major challenges in developing eRNA-targeted therapies. Finally, we propose future directions for advancing eRNA-based interventions in the treatment of human diseases, including cancer.