Enhancers are key noncoding DNA elements that control spatiotemporal gene expression programs by engaging cognate promoters through long-range chromosomal looping. Emerging evidence has shown that active enhancers and promoters are bidirectionally transcribed to generate vast enhancer RNA (eRNA) and promoter upstream antisense RNA (uaRNA). However, the functionality of those noncoding RNA transcripts and how they modulate transcription is poorly understood. We recently developed several RNA in situ conformation sequencing technologies, including RIC-seq and CRIC-seq, for the global profiling of RNA-RNA spatial interactions. We found that the functional connectivity of enhancers and promoters can be assigned using their pairwise-interacting RNAs. Importantly, these eRNA-uaRNA interactions are mediated by diverse RNA-binding proteins and appear required for long-range chromatin looping and transcriptional activation. Here, we analyze the largest RIC-seq and CRIC-seq datasets generated from multiple cell lines and identify tens of thousands of enhancer and promoter RNA interactions. These comprehensive enhancer-promoter RNA interaction maps enable us to unravel the enhancer and promoter communication principles and link many risk variants to disease genes. In this meeting, I would like to share our recent findings on how enhancers communicate with promoters via RNA-RNA interactions and how those RNA sequence variants that disrupt enhancer-promoter circuitry cause disease.