RNA polymerase II dynamics shape enhancer-promoter interactions

How enhancers control target gene expression over long genomic distances remains an important unsolved problem. Here we investigated enhancer-promoter communication by integrating data from nucleosome-resolution genomic contact maps, nascent transcription and perturbations affecting either RNA polymerase II (Pol II) dynamics or the activity of thousands of candidate enhancers. Integration of new Micro-C experiments with published CRISPRi data demonstrated that enhancers spend more time in close proximity to their target promoters in functional enhancer-promoter pairs compared to nonfunctional pairs, which can be attributed in part to factors unrelated to genomic position. Manipulation of the transcription cycle demonstrated a key role for Pol II in enhancer-promoter interactions. Notably, promoter-proximal paused Pol II itself partially stabilized interactions. We propose an updated model in which elements of transcriptional dynamics shape the duration or frequency of interactions to facilitate enhancer-promoter communication. Perturbation of RNA polymerase II (Pol II) via chemical inhibition or dTAG-induced degradation and analysis using Micro-C and run-on sequencing show that enhancer-promoter contacts are dependent on transcription and stabilized by paused RNA Pol II.

Automated summary

By integrating various experimental data, including nucleosome-resolution genomic contact maps, nascent transcription, and perturbations affecting RNA polymerase II dynamics or enhancer activity, this study investigates enhancer-promoter communication. The results demonstrate that functional enhancer-promoter pairs have longer proximity compared to nonfunctional pairs, partly due to factors unrelated to genomic position. Manipulation of transcription cycle reveals the key role of Pol II in enhancer-promoter interactions, with promoter-proximal paused Pol II partially stabilizing these interactions. An updated model is proposed to explain how transcriptional dynamics shape the duration or frequency of enhancer-promoter interactions to facilitate communication.