A transcription coupling model for how enhancers communicate with their target genes

How enhancers communicate with their target genes to influence transcription is an unresolved question of fundamental importance. Current models of the mechanism of enhancer–target gene or enhancer–promoter (E–P) communication are transcription-factor-centric and underappreciate major findings, including that enhancers are themselves transcribed by RNA polymerase II, which correlates with enhancer activity. In this Perspective, we posit that enhancer transcription and its products, enhancer RNAs, are elementary components of enhancer–gene communication. Specifically, we discuss the possibility that transcription at enhancers and at their cognate genes are linked and that this coupling is at the basis of how enhancers communicate with their targets. This model of transcriptional coupling between enhancers and their target genes is supported by growing experimental evidence and represents a synthesis of recent key discoveries.