Fluctuating Chromatin Facilitates Enhancer–Promoter Communication by Regulating Transcriptional Clustering Dynamics

Enhancers regulate gene expression by forming contacts with distant promoters. Phase-separated condensates or clusters formed by transcription factors (TFs) and cofactors are thought to facilitate these enhancer–promoter (E–P) interactions. Using polymer physics, we developed distinct coarse-grained chromatin models that produce similar ensemble-averaged Hi-C maps but with “stable” and “dynamic” characteristics. Our findings, consistent with recent experiments, reveal a multistep E–P communication process. The dynamic model facilitates E–P proximity by enhancing TF clustering and subsequently promotes direct E–P interactions by destabilizing the TF clusters through chain flexibility. Our study promotes physical understanding of the molecular mechanisms governing E–P communication in transcriptional regulation.