RNA polymerase II and PARP1 shape enhancer-promoter contacts

Metazoan cellular diversity and organismal complexity depend on the activity of gene-distal transcriptional enhancers. Since the landmark discovery of the SV40 enhancer more than 40 years ago, a key goal has been to understand the molecular basis by which enhancers and promoters are able to communicate across long stretches of DNA sequence. Here, I will present results from nucleosome-resolution Micro-C data of genomic contacts, nascent RNA sequencing, and CRISPR interference (CRISPRi) experiments testing nearly six thousand enhancer-promoter pairs. I will argue that enhancer regulation of gene promoters depends not only on enhancer-promoter interaction frequency, but also on how close they can reach in 3D space. Moreover, I will present new evidence that the tightly regulated pausing of RNA polymerase II near the transcription start sites of metazoan enhancers and promoters (Pol II pausing) stabilizes enhancer-promoter contacts. Finally, I will show that the enzymatic activity of poly (ADP-ribose) polymerase 1 (PARP1), an important regulator of transcription and chromatin in gene promoters, has a stabilizing effect on enhancer-promoter contacts that is independent of its effect on Pol II pausing. In light of these observation, I will discuss an updated model for enhancer-promoter communication in metazoan genomes.