Fig. 6: Model for enhancer–promoter interaction.

Higher-order chromatin boundaries are maintained by cohesin loops associated with convergent CTCF dimers. Within a domain, many enhancer–promoter contacts are associated with RAD21/CTCF peaks, and we suggest that similar cohesin loops are required for a subset of these interactions. At some enhancers (for example super-enhancers) a high concentration of factors such as BRD4 and Mediator drive the formation of phase condensates, and these may increase interactions with factors at the promoter, held nearby by cohesin loops. These interactions may be required to activate or increase transcription from the promoter. Upon addition of IBET, AT1, or 1,6-hexanediol, BRD4 and Mediator binding is reduced at the enhancer and phase condensates are dissolved, disrupting interaction with factors at the promoter. This disrupts gene expression, but does not affect enhancer–promoter proximity as the two loci remain held together by other factors, for example cohesin.