RAISE: A Phase Separation Model for Transcriptional Control in Mammals

这个RAISE奖项目的主要目标是发现哺乳动物基因调控的基本方面。许多患病的细胞状态（包括癌症和自身免疫）与由超级增强子（SE）调节的基因转录的异常调节相关，超级增强子（SE）是调节对健康和患病的细胞类型特异性过程重要的基因转录的大簇增强子（例如，癌症）状态。因此，所提出的基础研究对设计对人类健康有重大影响的疾病的治疗方法具有重要意义。这些研究的直接潜在影响涉及目前正在临床试验中测试的SE抑制剂，用于治疗癌症和其他疾病。这项工作也有一个重要的培训部分。 本科生研究是麻省理工学院实验室的一个组成部分。正式机制，如麻省理工学院本科生机会计划（UROP），麻省理工学院夏季研究计划和安进学者计划，为代表性不足的少数民族，将用于招募本科生到PI的实验室。一名PI还将参加ACCESS，这是麻省理工学院为代表性不足的少数民族学生举办的一个周末，旨在让他们了解研究生学习的机会。这项研究对科学和技术的影响将通过制作一个视频学习模块传播到更广泛的科学界，该模块针对广大的公民社区，特别是K-12教育受众。 麻省理工学院一直处于物理、生命和工程科学融合研究的中心。PI将教授课程，其中这一跨学科的工作将突出.超级增强子是由一个异常高密度的相互作用的分子占据，并能够驱动比典型的增强子更高水平的转录.一些证据表明，它们通过合作过程形成，SE比典型的增强子更容易受到通常与大多数增强子相关的组分的干扰。最近，PI提出相分离的多分子组装体调节SE的形成和功能（Cell，2017）。他们认为，一些与SE功能相关的谜题与这样一个模型是一致的。这些结果为探索相分离在哺乳动物基因控制中的作用提供了一个起点。通过将复杂的理论研究（植根于统计物理学）和生物学实验结合起来，PI现在的目标是研究他们的新提议，目的是为理解哺乳动物的基因调控建立一个概念框架，以及为什么SE进化为调控关键基因。因此，收集到的机制的见解也将适用于不同的过程中，在真核细胞介导的相分离的无膜细胞器。通过将植根于物理学和生物学的方法结合在一起，PI旨在解决以下重要问题：1）决定SE如何形成和发挥作用以调节哺乳动物基因转录的基本物理和生物学原理是什么？2]为什么在细胞身份中发挥最重要作用的基因进化成受SE调控？3]为什么癌细胞具有SE调节的癌基因，为什么这些癌基因对抑制某些转录调节因子的药物如此脆弱？为了回答这些问题，PI建议研究两个主要课题：1）了解相变的性质及其对基因调控的影响。2]了解超级增强子如何成核和形成。该RAISE项目由数学和物理科学理事会物理部的生命系统物理学计划、生物科学理事会分子和细胞生物科学部的细胞集群以及综合活动办公室共同资助。

The main goal of this RAISE Award project is to discover fundamental aspects of gene regulation in mammals. Many diseased cellular states (including cancer and autoimmunity) are associated with aberrant regulation of transcription of genes regulated by super-enhancers (SEs), large clusters of enhancers that regulate the transcription of genes important for cell type specific processes in both healthy and diseased (e.g., cancer) states.. Therefore, the proposed fundamental studies are of significance to the design of therapies for diseases that have a large toll on human health. The immediate potential impact of the studies concerns inhibitors of SEs that are currently being tested in clinical trials to treat cancer and other diseases. This effort also has an important training component. Undergraduate research is an integral part of labs at MIT. Formal mechanisms such as the MIT Undergraduate Opportunities Program (UROP), the MIT Summer Research Program and Amgen Scholars Program for underrepresented minorities, will be used to recruit undergraduates to the PI's laboratories. One PI will also participate in ACCESS, a weekend at MIT for underrepresented minority students designed to make them aware of opportunities for graduate study. The impact of this research on science and technology will be disseminated to the broader scientific community through the production of a video learning module targeted at both the broad community of citizens and specifically the K-12 educational audience. MIT has been at the epicenter of research at the convergence of the physical, life, and engineering sciences. The PIs will teach courses wherein this interdisciplinary work will be highlighted.Super-enhancers are occupied by an unusually high density of interacting molecules, and are able to drive higher levels of transcription than typical enhancers. Several lines of evidence suggest that they form via cooperative processes, and SEs are far more vulnerable than typical enhancers to perturbation of components that are commonly associated with most enhancers. Recently, the PIs proposed that a phase separated multi-molecular assembly regulates the formation and function of SEs (Cell, 2017). They suggested that some puzzles associated with SE function are consistent with such a model. These results provide just a starting point to explore the role of phase separation in gene control in mammals. By bringing together sophisticated theoretical studies (rooted in statistical physics) and biological experiments, the PIs now aim to study their novel proposal with the goal of developing a conceptual framework for understanding gene regulation in mammals, and why SEs evolved to regulate key genes. The mechanistic insights thus gleaned will also apply to diverse processes in eukaryotic cells that are mediated by phase separated membraneless organelles. By bringing together approaches rooted in physics and biology, the PIs aim to address the following significant questions: 1] What are the fundamental physical and biological principles that determine how SEs form and function to regulate gene transcription in mammals? 2] Why have genes with the most prominent roles in cell identity evolved to be regulated by SEs? 3] Why do cancer cells have SE-regulated oncogenes, and why are these so vulnerable to drugs that inhibit certain transcriptional regulators? In order to take steps toward answering these questions, the PIs propose to study two major topics: 1] Understanding the nature of the phase transition and its implications for gene regulation. 2] Understanding how super-enhancers nucleate and form.This RAISE project is being jointly funded by the Physics of Living Systems program in the Division of Physics in the Mathematical and Physical Sciences Directorate, by the Cellular Cluster in the Division of Molecular and Cellular Biosciences in the Biosciences Directorate, and by the Office of Integrative Activities.