ILLUMINATION OF CHROMATIN REGULATION VIA CHEMICAL CONTROLLED PROXIMITY

Project Summary The overarching goal of this project is to understand at a mechanistic level the chromatin regulatory pathways governing gene expression. To achieve this objective, we use chemically controlled proximity to allow for temporal and special control over specific chromatin regulatory enzymes. Our research group has made contributions to understanding the interplay between the heterochromatin protein 1 gene repression pathway and other chromatin regulators. In addition, we have a drug discovery program that has identified inhibitors of heterochromatin gene repression. We also have developed bifunctional molecules that work with catalytically inactive dCas9 to recruit endogenous chromatin regulatory enzymes to any site across the mammalian genome. Three main goals of this research program are: 1. Explore how heterochromatin gene repression is governed by two distinct H3K9 methylation binding proteins, 2. Develop approaches to visualize dynamic heterochromatin gene repression in real time at the single cell level 3. Study chromatin dynamics in real time with bifunctional compounds to recruit endogenous enzymes to specific loci. Over the course of this grant our research group will continue to advance our understanding of the mechanisms of heterochromatin gene repression using unique chemically based technologies. We also will further advance areas we have pioneered developing bifunctional small molecules to explore the capture and retargeting of endogenous chromatin regulators as an approach to understanding mammalian genome regulation.