Mechanisms and impacts of chromatin looping

Project Abstract Chromatin looping is thought to play a critical role in gene regulation, human development, and response to external stimuli by connecting regulatory loci with gene promoters. Most chromatin loops are thought to form via loop extrusion; however, recent work has uncovered loops and other chromatin structures formed via phase separation. How these loops form and how they impact gene transcription and other phenotypes remains poorly understood in part because they have only been studied in a handful of contexts and in part because we lack the adequate tools to study them. The goal of this research is to develop new computational and experimental tools to study 3D chromatin structure and to apply these tools to understand the mechanisms and impacts of phase separation-driven chromatin loops. We will map and characterize phase separation- driven chromatin loops formed in response to various external stimuli (project 1). We will develop experimental tools to manipulate these loops and apply them to explore their mechanisms of formation, quantify their impact on gene transcription, and identify molecules that can disrupt them (project 2). And we will develop computational tools that will enable robust analysis, interpretation, and visualization of these newly discovered 3D chromatin structures (project 3). The results of this research will determine both the scope and general principles of phase separation-driven looping and provide new tools for the gene regulation community.