TAO Yue-Zhu, YU Xiu-Chong, LIAO Qi
Enhancer RNA (eRNA) is a class of non-coding RNAs transcribed from enhancer regions, serving not only as markers of enhancer activity but also as functional executors in transcriptional regulation. Characteristic features of eRNAs include bidirectional transcription, 5′ capping, general lack of splicing, frequent absence of a poly(A) tail, and low nuclear stability. The transcription initiation and termination of eRNAs are regulated at multiple levels: histone modifications such as histone H3 lysine 27 acetylation (H3K27ac) act as key markers of enhancer activation and work in concert with the mediator complex, transcription factors (TFs), and other co-activators to recruit RNA polymerase Ⅱ (Pol Ⅱ) to enhancers, thereby initiating eRNA transcription. Meanwhile, the integrator complex and the polymerase-associated factor 1 complex (PAF1C) mediate the cleavage of nascent transcripts, leading to early transcription termination. Additionally, m6A post-transcriptional modification, through the reader protein YTH domain-containing protein 1 (YTHDC1), regulates eRNA stability, liquid-liquid phase separation (LLPS), and functional output. Functionally, synthesized eRNAs can act as molecular scaffolds to recruit chromatin remodelers such as CREB binding protein/E1A binding protein p300 (CBP/p300), bromodomain-containing protein 4 (BRD4), and the SWI/SNF complex, promoting local chromatin opening and three-dimensional conformational rearrangements. Moreover, eRNAs regulate gene expression in both cis and trans by modulating Pol Ⅱ pause-release, facilitating the formation and stabilization of enhancer-promoter (E-P) loops, and participating in the establishment of R-loop structures. In cancer, eRNAs are frequently dysregulated; they can upregulate oncogenes, suppress tumor suppressor genes, reshape the tumor microenvironment (TME), and regulate immune checkpoint (IC) molecules, thereby influencing tumor proliferation, metastasis, and response to immunotherapy. Although eRNAs show great potential as diagnostic and prognostic biomarkers and therapeutic targets, their low abundance, transient expression, and challenges in in vivo delivery remain major obstacles to clinical translation. With advancing technologies—such as single-cell multi-omics, spatial transcriptomics, CRISPR-dCas13-based real-time imaging, AI-driven data integration, and novel drug delivery platforms—we are poised to systematically decipher the spatiotemporal functional landscape of eRNAs and advance their translation into precision medicine applications. This review systematically summarizes the molecular features and multi-layer regulatory networks of eRNAs, their roles in cancer, the challenges and strategies for clinical translation, and future research directions.
