Theoretical Modeling of Protein-Driven Chromosomal Dynamics and Biological Function

蛋白质驱动的染色体动力学和生物功能的理论模型

• 批准号: 1707751
• 负责人: Andrew Spakowitz
• 金额: $ 45.55万
• 依托单位: Stanford University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1707751&HistoricalAwards=false
• 关键词: Theoretical; Modeling; Protein; Driven; Chromosomal

This research project aims to enhance the use of theoretical and simulation approaches to address critical biological problems that have both fundamental and practical impact. The models used in this project draw from the fields of polymer and soft-materials physics and infuse novel physical concepts and understanding into problems involving living cells and organisms. The engagement of both in vitro and in vivo experimental measurements will provide guidance on the implementation of quantitative theory into practical biological problems. Results from this program will be widely disseminated through publications, conferences, and an online repository of simulation tools as well as descriptions, press releases, and educational tools for use by the broad scientific community and the general public. The lab of the PI is an ideal environment for training quantitative biologists who are capable of tackling a diverse range of fundamental and applied problems in living systems, and the lab's commitment to diversity and educational development has led to alumni of the group who are making major contributions to both academic and industrial research. This program develops and implements laboratory science and engineering teaching modules for the education of high school students who are being treated for childhood cancer and other illnesses. This program is piloted at the Hospital School at the Lucile Packard Children's Hospital, and the PI engages undergraduate and graduate students at Stanford to develop the program, resulting in an exciting opportunity for students to enrich their educational experience with broader outreach. Ongoing efforts aim to broadly disseminate this program nationally as a general laboratory science curriculum for hospital-school education.Prokaryotic and eukaryotic cells have the daunting task of compactly packaging their immense genome while simultaneously maintaining gene regulatory control and the ability for chromosomal DNA to be replicated and segregated in a robust manner. Chromosomal DNA within living cells is manipulated and accessed by a host of proteins that perform numerous functions that are orchestrated throughout the cellcycle. The physical manipulation of chromosomal DNA is central to its function, and achieving a fundamental quantitative framework for predicting and interpreting chromosomal organization and dynamics would be instrumental to our understanding of living systems. This research program aims to tackle three major biological processes involving chromosomal DNA in prokaryotic cells: regulation, segregation, and organization. These efforts are delineated into three complementary thrusts that establish fundamental physical insight into the orchestrated function of proteins that influence chromosomal organization and dynamics. In Thrust 1, the PI addresses the impact of DNA supercoiling on gene regulation. This effort focuses on two prototypical regulatory proteins (Lac repressor and ë repressor) that serve as examples of regulatory proteins that engage DNA at multiple sites to form a regulatory complex. Cellular control of supercoiling elicits major changes in gene regulation, and this thrust will directly address how topoisomerases and regulatory proteins orchestrate their function. Thrust 2 aims to address segregation of DNA through the ParABS system's highly conserved prokaryotic segregation apparatus. The mysterious function of this system is unlike motor or cytoskeletal proteins in that there is no obvious force generating function. The efforts will aim to resolve how temporal correlations in chromosomal dynamics result in directed motion in a burning-bridge mechanism for the ParABS system. In Thrust 3, the PI will tackle the interplay between RNA polymerase and condensin in dictating chromosomal organization. Active forces generated by RNA polymerase displace proteins along DNA, and the resulting impact of these nonequilibrium processes on chromosomal organization will be addressed in this thrust, providing new physical insight into the formation and maintenance of organized domains within the cell.This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Genetic Mechanisms Cluster in the Division of Molecular and Cellular Biosciences.

该研究项目旨在加强理论和模拟方法的使用，以解决具有根本和实际影响的关键生物学问题。该项目中使用的模型来自聚合物和软材料物理学领域，并将新的物理概念和理解注入到涉及活细胞和生物体的问题中。在体外和体内的实验测量的参与将提供定量理论到实际的生物学问题的实施指导。该计划的结果将通过出版物、会议和模拟工具的在线存储库以及描述、新闻稿和教育工具广泛传播，供广大科学界和公众使用。PI的实验室是培养定量生物学家的理想环境，这些生物学家能够解决生命系统中各种各样的基本和应用问题，实验室对多样性和教育发展的承诺导致了该集团的校友为学术和工业研究做出了重大贡献。该计划开发和实施实验室科学和工程教学模块，用于正在接受儿童癌症和其他疾病治疗的高中生的教育。该计划在Lucile Packard儿童医院的医院学校进行试点，PI与斯坦福大学的本科生和研究生合作开发该计划，为学生提供了一个令人兴奋的机会，通过更广泛的推广来丰富他们的教育经验。目前正在努力的目标是在全国范围内广泛传播这一计划，作为医院-学校教育的一般实验室科学课程。原核细胞和真核细胞有艰巨的任务，即在保持基因调控控制和染色体DNA以稳健的方式复制和分离的能力的同时，将其巨大的基因组进行复杂包装。活细胞内的染色体DNA由许多蛋白质操纵和访问，这些蛋白质在整个细胞周期中执行许多功能。染色体DNA的物理操作是其功能的核心，实现预测和解释染色体组织和动力学的基本定量框架将有助于我们理解生命系统。该研究计划旨在解决原核细胞中涉及染色体DNA的三个主要生物学过程：调节，分离和组织。这些努力被描绘成三个互补的推力，建立基本的物理洞察到影响染色体组织和动力学的蛋白质的协调功能。在Thrust 1中，PI解决了DNA超螺旋对基因调控的影响。这项工作集中在两个原型的调节蛋白（Lac阻遏物和ë阻遏物），作为调节蛋白的例子，在多个位点结合DNA，形成一个调控复合物。细胞对超螺旋的控制引起基因调控的重大变化，这一推力将直接解决拓扑异构酶和调控蛋白如何协调它们的功能。推力2旨在通过ParABS系统的高度保守的原核分离装置解决DNA的分离。这个系统的神秘功能不同于马达或细胞骨架蛋白，因为没有明显的力产生功能。这些努力的目的是解决如何在染色体动力学的时间相关性导致定向运动的烧桥机制的ParABS系统。在第3个目标中，PI将解决RNA聚合酶和凝聚素之间在决定染色体组织方面的相互作用。由RNA聚合酶产生的主动力使蛋白质沿着DNA移位，这些非平衡过程对染色体组织的影响将在本书中讨论，为细胞内有组织结构域的形成和维持提供新的物理见解。该项目由物理学系生命系统物理学项目和分子生物学系遗传机制组联合支持。和细胞生物科学公司

项目成果

Physical modeling of the heritability and maintenance of epigenetic modifications

• DOI: 10.1073/pnas.1920499117
• 发表时间: 2020-08
• 期刊: Proceedings of the National Academy of Sciences
• 作者: Sarah H. Sandholtz;Quinn MacPherson;A. Spakowitz

Geometrical Heterogeneity Dominates Thermal Fluctuations in Facilitating Chromatin Contacts

• DOI: 10.1103/physrevlett.123.208103
• 发表时间: 2019-11-15
• 期刊: PHYSICAL REVIEW LETTERS
• 影响因子: 8.6
• 作者: Beltran, Bruno;Kannan, Deepti;Spakowitz, Andrew J.
• 通讯作者: Spakowitz, Andrew J.

Physical modeling of the spreading of epigenetic modifications through transient DNA looping

通过瞬时 DNA 环传播表观遗传修饰的物理模型

• DOI: 10.1088/1751-8121/ab41d2
• 发表时间: 2019
• 期刊: Journal of Physics A: Mathematical and Theoretical
• 作者: Sandholtz, Sarah H;Beltran, Bruno G;Spakowitz, Andrew J
• 通讯作者: Spakowitz, Andrew J

Brachiation of a polymer chain in the presence of a dynamic network

• DOI: 10.1103/physreve.102.020501
• 发表时间: 2020-08-06
• 期刊: PHYSICAL REVIEW E
• 影响因子: 2.4
• 作者: Cai, Pamela C.;Krajina, Brad A.;Spakowitz, Andrew J.
• 通讯作者: Spakowitz, Andrew J.

Transient Anomalous Diffusion in a Heterogeneous Environment

• DOI: 10.3389/fphy.2019.00119
• 发表时间: 2019-09
• 期刊: Frontiers in Physics
• 影响因子: 3.1
• 作者: A. Spakowitz