RAISE: A Phase Separation Model for Transcriptional Control in Mammals

RAISE：哺乳动物转录控制的相分离模型

• 批准号: 1743900
• 负责人: Arup Chakraborty
• 金额: $ 100万
• 依托单位: Massachusetts Institute of Technology
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1743900&HistoricalAwards=false
• 关键词: RAISE; Phase; Separation; Model; Transcriptional

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.

该 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）与超级增强子（SE）调节的基因转录异常调节有关，超级增强子是一大群增强子，可调节对健康和患病（例如癌症）状态下细胞类型特定过程重要的基因转录。因此，所提出的基础研究对于设计针对对人类健康造成重大损失的疾病的疗法具有重要意义。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，以治疗癌症和其他疾病。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的一个组成部分。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针对代表性不足的少数族裔的安进学者计划等正式机制将用于招募本科生加入 PI 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族裔学生举办的周末活动，旨在让他们了解研究生学习的机会。这项研究对科学技术的影响将通过制作针对广大公民群体，特别是 K-12 教育受众的视频学习模块，传播到更广泛的科学界。 麻省理工学院一直处于物理、生命和工程科学融合研究的中心。 PI 将教授强调这种跨学科工作的课程。超级增强子由异常高密度的相互作用分子占据，并且能够比典型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 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件的扰动。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）。他们认为与 SE 函数相关的一些谜题与这样的模型是一致的。这些结果只是探索相分离在哺乳动物基因控制中的作用的起点。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，目标是开发一个概念框架来理解哺乳动物的基因调控，以及为什么 SE 进化来调控关键基因。由此收集到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多种过程。通过汇集源于物理学和生物学的方法，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会进化为受 SE 调控？ 3] 为什么癌细胞具有 SE 调节的癌基因，以及为什么这些细胞如此容易受到抑制某些转录调节因子的药物的影响？为了采取措施回答这些问题，PI 建议研究两个主要主题： 1] 了解相变的本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。这个 RAISE 项目由数学和物理科学局物理司生命系统物理项目、生物科学局分子和细胞生物科学司细胞簇以及综合活动办公室共同资助。

项目成果

Enhancer Features that Drive Formation of Transcriptional Condensates

• DOI: 10.1016/j.molcel.2019.07.009
• 发表时间: 2019-08-08
• 期刊: MOLECULAR CELL
• 影响因子: 16
• 作者: Shrinivas, Krishna;Sabari, Benjamin R.;Chakraborty, Arup K.
• 通讯作者: Chakraborty, Arup K.