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，具有猝灭的无序，复杂的拓扑性质，并被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在生命系统物理学方面具有互补专业知识的领导小组的理论和实验生物物理学的方法来研究染色体物理学。巴黎国家研究中心的库伦实验室率先使用了染色体的机械扰动，即通过外部磁场在活细胞内移动基因组位置。这种微扰在方法上是新颖的，可以提供关于染色体物理状态和动态的独特信息。从这些测量中获得洞察力需要开发染色体组织的物理模型。麻省理工学院的米尔尼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。库伦和米尔尼实验室一直在合作这一项目，并发表了第一篇提供大量初步数据支持这一项目的论文。目前对染色体组织的理解主要是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置的能力为回答长期存在但尚未回答的问题提供了一个独特的句柄：i)染色质的物理性质是什么？Ii)染色质中的分子作用力有多大？Iii)维持染色体区域的机制是什么？这种由理论驱动的染色体机械探测将使人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的新的物理机制。该项目将继续开展推广活动，包括由Mirny和Coulon联合在波士顿和法国区域举办的公开讲座；与Actin Art Association和居里研究所的Espprits Curieux倡议联合开发一本关于染色体和细胞核物理学的儿童书籍；以及通过MIT PRIMES计划让高中生参与研究。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.