Direct observation of a condensate effect on super-enhancer controlled gene bursting

Abstract

Enhancers are distal DNA elements believed to loop and contact promoters to control gene expression. Recently, we found diffraction -sized transcriptional condensates at genes controlled by clusters of enhancers (super -enhancers). However, a direct function of endogenous condensates in controlling gene expression remains elusive. Here, we develop live -cell super -resolution and multi -color 3D -imaging approaches to investigate putative roles of endogenous condensates in the regulation of super -enhancer controlled gene Sox2. In contrast to enhancer distance, we find instead that the condensate's positional dynamics are a better predictor of gene expression. A basal gene bursting occurs when the condensate is far (>1 mm), but burst size and frequency are enhanced when the condensate moves in proximity (<1 mm). Perturbations of cohesin and local DNA elements do not prevent basal bursting but affect the condensate and its burst enhancement. We propose a three-way kissing model whereby the condensate interacts transiently with gene locus and regulatory DNA elements to control gene bursting.