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）是令人着迷的物理系统，具有猝灭无序，复杂的拓扑性质，并被活跃过程驱动远离平衡。在这个项目中，研究人员将通过整合两个领先小组的理论和实验生物物理学方法，以及在生命系统物理学方面的互补专业知识，来研究染色体物理学。法国巴黎科学研究中心的库伦实验室率先利用外部磁场移动活细胞内的基因组位点，对染色体进行机械扰动。这种扰动在方法上是新颖的，可以提供关于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发展染色体组织的物理模型。麻省理工学院的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。Coulon和Mirny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来支持这个项目。目前对染色体组织的了解主要是基于通过非扰动实验获得的数据。在活细胞中施加力和机械操纵染色体位点的能力为回答长期存在但尚未解决的问题提供了一个独特的解决方案：1)染色质的物理性质是什么？ii)染色质中的分子作用力有多强？iii)染色体区域维持的机制是什么？这种由理论驱动的染色体机械探测将使我们能够理解染色体的物质性质，并揭示染色体组织和动力学背后的新物理机制。该项目将开展外联活动，包括由Mirny和Coulon联合在波士顿和revzionÎle-de-France举办的公开讲座；与Actin Art协会和居里研究所的“Esprits Curieux”倡议合作，编写了一本关于染色体和细胞核物理学的儿童书籍；以及让高中生参与MIT PRIMES项目的研究。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。

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.