Illuminating transcriptional condensates using an integrated approach

项目摘要 基因调控是人类功能的各个方面的基础，在这一过程中的错误是 包括癌症在内的许多疾病的关键驱动因素。正确的基因表达需要大量的 蛋白质的组装和功能在一个高度协调的方式，但如何实现这一点是 还是不明白最近的研究表明，一些转录调控因子形成动态的 高局部浓度的组装体，称为转录浓缩物或枢纽。这些 凝聚物由弱多价相互作用驱动，具有生物物理性质， 调节机制不同于长期研究的“锁和钥匙”型的高亲和力 交互.因此，转录缩合物的发现提供了一种新的分子生物学方法。 原则来解释如何组织转录。然而，目前还不清楚， 转录浓缩物，它们是如何调节和失调的，以及它们如何影响 在发育和疾病中的基因控制。这主要是由于缺乏实验性的 精确控制冷凝物形成及其特性的策略， 机械式的审讯该项目通过利用 自然发生的疾病突变。我们发现了一系列致癌突变， 促进转录浓缩物异常形成的染色质调节因子。这些 “获得性”冷凝物与致癌基因激活和肿瘤发生密切相关， 提供了将异常冷凝物形成与人类疾病联系起来的第一个实例之一。 利用这些突变作为垫脚石，该项目旨在开发一个更深入， 广泛的理解转录浓缩物，并建立其失调作为一个新的 致病机理具体而言，我们将提出三个主要问题：（1）如何 转录缩合物在分子水平上形成？(2)监管职能是什么 是由转录浓缩物实现的吗(3)转录浓缩物可以治疗吗 针对？我们将整合结构生物学、单分子 成像、基因调控、表观遗传学、癌症生物学和高通量药物发现， 来解决这些问题。该项目的成功完成将提供明确的证据， 建立基因控制的新模型所需的机械见解。它也有可能 改变了我们对疾病中基因失调的认识和定位。理想的实验 我们发现的系统和我实验室的广泛专业知识使我们处于一个独特的位置， 这个雄心勃勃但又急需的研究项目

Project Summary Gene regulation is fundamental for every aspect of human function and errors in this process are key drivers for many diseases, including cancer. Proper gene expression requires a large number of proteins to assemble and function in a highly coordinated manner, but how this is achieved is still not understood. Recent studies revealed that some transcriptional regulators form dynamic high local concentration assemblies termed transcriptional condensates or hubs. These condensates are driven by weak multivalent interactions, which have biophysical properties and regulatory mechanisms distinct from the long-studied ‘lock and key’-type of high-affinity interactions. As such, the discovery of transcriptional condensates offers a new molecular principle to explain how transcription is organized. However, it remains unclear how exactly transcriptional condensates from, how they are regulated and dysregulated, and how they impact gene control during development and in diseases. This is largely due to the lack of experimental strategies to precisely control condensate formation and its properties for functional and mechanistic interrogations. This project uniquely addresses these major gaps by leveraging naturally occurring disease mutations. We discovered a series of oncogenic mutations in a chromatin regulator that promote aberrant formation of transcriptional condensates. These ‘acquired’ condensates strongly correlated with oncogenic gene activation and tumorigenesis, providing one of the first examples linking aberrant condensate formation to human disease. Using these mutations as the stepping-stone, this project aims to develop a more in-depth and broad understanding of transcriptional condensates and establish their dysregulation as a new pathognenic mechanism. Specifically, we will ask three major questions: (1) How do transcriptional condensates form at the molecule level? (2) What are the regulatory functions enabled by transcriptional condensates? (3) Can transcriptional condensates be therapeutically targeted? We will integrate cutting-edge approaches in structural biology, single-molecule imaging, gene regulation, epigenetics, cancer biology, and high-throughput drug discovery to address these questions. Successful completion of this project would offer definitive evidence and mechanistic insights needed to establish a new model of gene control. It also has the potential to transform how we think about and target gene dysregulation in diseases. The ideal experimental system we discovered and extensive expertise of my lab put us in a unique position to embark on this highly ambitious but urgently needed research program.