Theoretical and Computational Modeling of Supercoiling, Topology, and Active Fluctuations in Chromosomal Organization and Dynamics

本研究计划建立新的方法来分析和预测活细胞中的染色体组织和动力学。此外，本研究计划的基础理论发展可转移到由非平衡主动力驱动的广泛生物过程中。此外，PI将解决的特定生物过程将为我们理解染色体组织和功能的核心现象提供新的基本见解。生殖和表观遗传调控是人类生物学中两个最重要的特征。这个研究项目为我们如何繁殖以及我们如何建立和维持多细胞编程的分子起源带来了定量的物理见解，为解释实验测量提供了基本的见解和预测工具。这个研究项目是由几个关键的可交付成果定义的，这些成果提供了影响一系列社区的教育资源。教育计划包括建立LABScI（扩展科学教学的实验室活动），为正在接受儿童癌症和其他疾病治疗的高中生开发和实施实验室科学和工程教学模块。LABScI项目由本科生和研究生共同开发教学模块，为学生提供了丰富教育经验的机会。PI将与斯坦福大学教育学院合作，扩大LACScI项目，并开发有效整合在线教育和动手实验活动的教育材料。PI实验室的新软件开发旨在巩固基于物理的建模、基因组和生物信息学分析以及数据科学方法的计算方法。与软件开发相结合的是提供有助于实现这些不同方法的教育资源的努力。教育方面的新努力旨在展示如何有效地整合基于物理和数据科学的方法，作为生物分析的补充工具。人类细胞中所有生物过程的指令都包含在染色体中，染色体的总DNA长度大约为一米。这些巨大的DNA聚合物必须能够组织和重新排列，以响应对生物功能至关重要的细胞周期事件。pi现有的聚合物动力学理论为描述染色体行为提供了一个起点，但是一系列不同的生物物理机制有助于活细胞中的行为，而这些行为目前还没有在现有的理论模型中被捕获。大量的实验观察表明，染色体组织和动力学受到酶的显著影响，这些酶操纵DNA扭曲和超缠绕，减轻缠结和结，并贡献活跃的生物力量。这个研究计划将建立一个理论和计算框架来预测和分析这些染色体行为的关键生物物理驱动因素。在建立可转移到广泛生物过程的理论时，PI将重点关注以下三个关键的细胞周期事件：减数分裂期间同源染色体的配对，RNA转录期间引入扭转和超卷曲，以及细胞分裂后染色体区域的建立。在这个项目中，PI将解决在为生命系统建立物理框架方面的主要挑战之一——为非平衡物质建立统一的预测理论。在这项工作中，他将发展一种新的活性布朗物质理论，为预测瞬时酶波动在驱动生物过程中的作用提供明确的途径。这一理论方法揭示了一个流行的概念——时间依赖温度——它作为一个巩固框架，用于捕捉活生物系统中的非平衡行为，并将利用这一理论方法在特定问题上，这是对染色体生物物理学理解的核心。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This research program establishes new methods to analyze and predict chromosomal organization and dynamics in living cells. Furthermore, the foundational theoretical development in this research program is transferable to a broad range of biological processes that are driven by non-equilibrium active forces. In addition, the specific biological processes that the PI will tackle provide new fundamental insight in top phenomena that are central to our understanding of chromosomal organization and function. Reproduction and epigenetic regulation represent two of the most critical defining features in human biology. This research program brings quantitative physical insight into the molecular origins of how we reproduce and how we establish and maintain our multi-cellular programming, providing fundamental insight and predictive tools for interpreting experimental measurements. This research program is defined by several key deliverables that provide educational resources that impact a range of communities. The educational program includes the establishment of LABScI (Laboratory Activities for Broadened Scientific Instruction) to develop and implement laboratory science and engineering teaching modules for high school students that are being treated for childhood cancer and other illnesses. The LABScI program engages undergraduate and graduate students to develop the teaching modules, resulting in an exciting opportunity for students to enrich their educational experience. The PI will partner with the School of Education at Stanford University to expand the LACScI program and develop educational materials that effectively integrate online education with hands-on laboratory activities. New software development in the PI's lab aims to consolidate computational approaches in physics-based modeling, genomic and bioinformatic analysis, and data-science methods. Coupled to the software development is an effort to provide educational resources that aid the implementation of these disparate approaches. New efforts in education aim to demonstrate how to effectively integrate physics-based and data-science approaches as complementary tools for biological analysis.The instructions for all biological processes in human cells are contained within chromosomes whose total DNA length is roughly one meter. These massive DNA polymers must be capable of organizing and rearranging in response to cell-cycle events that are central to biological function. The PIs existing theory of polymer dynamics provides a starting point for describing chromosomal behavior, but a range of distinct biophysical mechanisms contribute to the behavior in living cells that are not currently captured within the existing theoretical models. Numerous experimental observations demonstrate that chromosomal organization and dynamics are dramatically influenced by enzymes that manipulate DNA twist and supercoiling, mitigate entanglements and knots, and contribute active biological forces. This research program will establish a theoretical and computational framework for predicting and analyzing these critical biophysical drivers of chromosomal behavior. In establishing theory that is transferable to a broad range of biological processes, the PI will focus on the following three key cell-cycle events: pairing of homologous chromosomes during meiosis, introduction of twist and supercoiling during RNA transcription, and the establishment of chromosome territories after cell division. Within this program, the PI will tackle one of the prevailing challenges in establishing a physical framework for living systems—establishing a unified predictive theory for non-equilibrium matter. In this effort, he will develop a new theory of active-Brownian matter that provides a clear pathway for prediction of the role of transient enzymatic fluctuations in driving biological processes. This theoretical approach reveals a prevailing concept—the time-dependent temperature—that serves as a consolidating framework for capturing non-equilibrium behavior in living bio-logical systems, and will exploit this theoretical approach in specific problems that are central to the understanding of chromosomal biophysics.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.