NSF-ANR: Physics of chromosomes through mechanical perturbations

DNA分子不仅是遗传信息的载体，而且是超长的聚合物。这些聚合物（染色体）是迷人的物理系统，具有猝灭的无序性，复杂的拓扑性质，并由活性过程驱动远离平衡。在这个项目中，研究人员将通过整合两个领导小组的理论和实验生物物理学方法来研究染色体物理学，并在生命系统物理学方面具有互补的专业知识。法国国家科学研究中心巴黎的库隆实验室率先使用染色体的机械扰动，通过外部磁场移动活细胞内的基因组位点。这样的扰动是方法新颖的，可以提供有关染色体的物理状态和动力学的独特信息。从这些测量中获得见解需要开发染色体组织的物理模型。MIT的Mirny实验室一直在开发染色体的聚合物模型，旨在了解染色体折叠的原理和机制。库伦实验室和米尔尼实验室一直在这个项目上合作，并发表了第一篇论文，提供了广泛的初步数据，以支持这个项目。目前对染色体组织的了解很大程度上基于通过非微扰实验获得的数据。在活细胞中施加力和机械操纵染色体位点的能力提供了一个独特的手柄来回答长期存在但尚未回答的问题：i）染色质的物理性质是什么？2.染色质中的分子力有多强？iii）什么机制是维持染色体区域的基础？ 这种理论驱动的染色体机械探测将允许理解染色体的物质性质，并揭示染色体组织和动力学的新物理机制。该项目将开展外联活动，包括米尔尼和库隆在波士顿和法兰西大区联合举办公开讲座;与肌动蛋白艺术协会和居里研究所的“好奇心”倡议联合编写一本关于染色体和细胞核物理学的儿童读物;该奖项反映了NSF的法定使命，并通过评估被认为值得支持使用基金会的知识价值和更广泛的影响审查标准。

DNA molecules are not only carriers of genetic information but are also exceedingly long polymers. These polymers (chromosomes) are fascinating physical systems with quenched disorder, complex topological properties, and driven far from equilibrium by active processes. In this project the investigators will examine the Physics of Chromosomes by integrating approaches of theoretical and experimental biophysics of two leading groups with complementary expertise in Physics of Living Systems. The Coulon lab, at CNRS Paris, has pioneered the use of mechanical perturbation of chromosomes by moving a genomic locus within a living cell by external magnetic field. Such perturbations are methodologically novel and can provide unique information about the physical state and dynamics of chromosomes. Gaining insights from these measurements requires development of physical models of chromosome organization. The Mirny lab, at MIT, has been developing polymer models of chromosomes aiming to understand principles and mechanisms underlying chromosomes folding. The Coulon and the Mirny labs have been collaborating on this project and have published the first paper that provides extensive Preliminary Data in support of this project. Current understanding of chromosome organization is largely based on data obtained through non-perturbative experiments. The ability to apply forces and mechanically manipulate chromosomal loci in a living cell provide a unique handle to answer long standing –but yet unanswered– questions: i) What is the physical nature of chromatin? ii) How strong are molecular forces in the chromatin? iii) What mechanism underlies maintenance of chromosomal territories? This theory-driven mechanical probing of chromosomes will allow understanding of the material nature of chromosomes and uncovering new physical mechanisms underlying chromosome organization and dynamics. This project will pursue outreach activities that include Public lectures in Boston and région Île-de-France given jointly by Mirny and Coulon; development of a children's book on physics of chromosomes and the nucleus, jointly with Actin Art association and the ‘Esprits Curieux’ initiative of the Institut Curie; and the involvement of high school students in research through MIT PRIMES program.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.