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。许多病变细胞状态（包括癌症和自身免疫）与由超级增强子（se）调控的基因转录的异常调节有关，超级增强子（se）是调节健康和病变（例如癌症）状态中对细胞类型特异性过程重要的基因转录的大簇增强子。因此，提出的基础研究对设计对人类健康造成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用于治疗癌症和其他疾病的se抑制剂。这项工作还有一个重要的培训组成部分。本科生研究是麻省理工学院实验室不可分割的一部分。麻省理工学院本科生机会计划（UROP）、麻省理工学院暑期研究计划和针对少数族裔的安进学者计划等正式机制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少数族裔学生设计的一个周末活动，旨在让他们意识到研究生学习的机会。这项研究对科学和技术的影响将通过制作一个针对广大公民社区，特别是K-12教育受众的录象学习模块，传播给更广泛的科学界。麻省理工学院一直处于物理、生命和工程科学融合的研究中心。pi将教授强调跨学科工作的课程。超级增强子被异常高密度的相互作用分子占据，并且能够比典型的增强子驱动更高水平的转录。一些证据表明它们是通过合作过程形成的，并且se远比典型的增强子更容易受到通常与大多数增强子相关的成分的扰动。最近，pi提出相分离的多分子组装调节SEs的形成和功能（Cell, 2017）。他们认为，与SE功能相关的一些谜题与这样的模型是一致的。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）和生物实验结合起来，pi现在的目标是研究他们的新提议，目的是建立一个理解哺乳动物基因调控的概念框架，以及为什么SEs进化到调节关键基因。由此收集的机制见解也将适用于真核细胞中由相分离的无膜细胞器介导的各种过程。通过将根植于物理学和生物学的方法结合起来，pi旨在解决以下重要问题：1]决定se如何形成和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]为什么在细胞特性中发挥最重要作用的基因进化为受SEs调控？[3]为什么癌细胞有硒调节的癌基因，为什么这些基因对抑制某些转录调节因子的药物如此脆弱？为了采取措施回答这些问题，pi建议研究两个主要主题：1]理解相变的本质及其对基因调控的影响。了解超级增强剂如何成核和形成。该RAISE项目由数学和物理科学理事会物理系的生命系统物理学项目、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.