Mechanisms of transcription control by distal enhancers from single-gene nanoscopy.
Distal enhancers activate genes over vast genomic distances, but how this communication occurs and what signals are transmitted are poorly understood. Using real-time single-gene nanoscopy and targeted perturbations, we define physical parameters and mechanisms of enhancer-promoter communication. We find that productive interactions are dynamic, occur at a proximity of ≲100 nm, and are coordinated with transcriptional bursts. Enhancers and promoters find one another not only through passi
Distal enhancers activate genes over vast genomic distances, but how this communication occurs and what signals are transmitted are poorly understood. Using real-time single-gene nanoscopy and targeted perturbations, we define physical parameters and mechanisms of enhancer-promoter communication. We find that productive interactions are dynamic, occur at a proximity of ≲100 nm, and are coordinated with transcriptional bursts. Enhancers and promoters find one another not only through passive diffusion; we often directly observe them being actively brought together by cohesin-mediated loop extrusion, which is a key determinant of transcriptional burst frequency. We also discover that specific general transcription factors (GTFs) of RNA polymerase II machinery are key to initiating transcriptional bursts, and enhancer-promoter interactions activate bursting by embedding the promoter within GTF clusters that form at the enhancers. Our results resolve the molecular and biochemical signals involved in long-range gene activation and elucidate the biophysical mechanisms for their transmission from the enhancer to the promoter.
