ILLUMINATION OF CHROMATIN REGULATION VIA CHEMICAL CONTROLLED PROXIMITY

项目摘要 这个项目的首要目标是在机械学水平上理解染色质 调控基因表达的途径。为了实现这一目标，我们使用 化学控制的接近，允许对特定的时间和特殊控制 染色质调节酶。我们的研究小组在以下方面做出了贡献 了解异染色质蛋白1基因抑制之间的相互作用 途径和其他染色质调节剂。此外，我们还有一个药物发现计划 这已经确定了异染色质基因抑制的抑制剂。我们还开发了 与催化失活的dCas9一起工作以招募内源的双功能分子 染色质调节酶连接到哺乳动物基因组中的任何位置。三大主线 这项研究的目标是：1.探索异染色质基因抑制是如何 由两个不同的H3K9甲基化结合蛋白控制，2.开发方法来 实时可视化单细胞水平的动态异染色质基因抑制3。 用双功能化合物实时研究染色质动力学以招募内源 酶与特定的基因座相关联。在这笔赠款期间，我们的研究小组将继续 促进我们对异染色质基因抑制机制的理解 独特的基于化学的技术。我们还将进一步推进我们已有的领域 率先开发双功能小分子探索捕获和重定向 内源性染色质调节剂作为了解哺乳动物的一种方法 基因组调控。

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.