Polymeric mechanism of enhancer-promoter cooperativity in transcriptional bursting

Emerging evidence suggest that gene expression is controlled though the modulation of transcriptional bursting across species. However, the underlying regulatory mechanisms remain largely uncertain. Recent live-imaging studies have reported that transcription factors (TFs) form a cluster at enhancers just prior to gene activation, thereby locally concentrating the active transcription machinery. This process is thought to be mediated by multivalent interaction between Mediator recruited by TFs. Conversely, transcription itself is also suggested that to influence the assembly of the TF clustering, implicating the presence of a feedback mechanism. To understand the theoretical framework underlying the interplay between TF clustering and transcription, we here develop a polymer micelle model of transcriptional bursting. With this model, multiple RNA polymerase II (Pol II) molecules loaded to the promoter, together with enhancer-bound Mediator, assemble a micelle-like structure due to their connectivity via DNA when the chromatin fiber connecting enhancer and promoter adopts closed conformation, analogous to polysoap micelle. This assembly further recruits freely diffusing Pol II and Mediator in the nucleoplasm even at low concentration up to the optimal size. Our theoretical framework enables quantitative prediction of how dynamic transitions of enhancer-promoter conformation and the stability of the micelle impact the kinetics of transcriptional bursting.