Physics of Chromosomes

染色体物理学

• 批准号: 1504942
• 负责人: Leonid Mirny
• 金额: $ 45万
• 依托单位: Massachusetts Institute of Technology
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1504942&HistoricalAwards=false
• 关键词: Physics; Chromosomes

Twenty-three pairs of human chromosomes contain two meters of DNA. These long DNA molecules are folded inside a nucleus of a human cell that is about 5 microns in diameter. Chromosomes are not only carriers of our genetic information, but are also fascinating polymer systems with an organization that allows rapid packing and unpacking during the cell cycle and easy access to genetic information for reading and copying. This study will elucidate the physical principles that govern chromosome organization, an emerging frontier in the Physics of Living Systems. The investigators will focus on the development of polymer models of human chromosomes and use these models to elucidate principles of genome organization in 3 dimensions during interphase. Recently developed experimental techniques provide a wealth of information about chromosomal interactions and reveal multiple levels of chromosome organization, each with its unique physical characteristics: at large scales, chromosomes are organized into alternating active and inactive chromatin compartments; at smaller scales these are partitioned into subdomains. Little is know about possible physical mechanisms that drive such organization at each level and how the different levels are connected. Available data provide an excellent resource for developing and testing physical models of chromosome organization, allowing us to address a fundamental question: how is DNA folded inside human chromosomes? Activities for freshmen and high school students include (1) involving high-school students in cutting-edge research in our group through the highly successful MIT PRIMES; (2) involving MIT undergraduate students in our proposed research through the MIT Undergraduate Research Opportunities Program; (3) development of a new Freshmen Seminar in Quantitative Biology, aimed at training the next generation of MIT students with an appreciation and understanding of the role of physics in living systems.The PI will address many important and unexplored problems in Polymer Physics, such as the nature of non-equilibrium states that emerge upon decondensation, the role of topological constraints, and the effect of heteropolymeric interactions in formation of multiscale structures. The four specific aims of the project are (1) develop a non-equilibrium model of the polymer ensemble that characterizes a whole chromosome after decondensation from mitosis; (2) identify physical mechanisms and heteropolymeric interactions that can give rise to organization of human chromosomes into large (1-5Mb) compartments; (3) develop models of domain organization at a smaller (0.2-1Mb) level, and to elucidate heteropolymer characteristics that can underlie such organization; (4) develop a multiscale model that integrates these three levels of organization and can explain several features and characteristics of the Hi-C and microscopy data.

23对人类染色体含有两米长的DNA。这些长的DNA分子折叠在直径约5微米的人类细胞核内。染色体不仅是我们遗传信息的载体，而且还是迷人的聚合物系统，其组织允许在细胞周期期间快速打包和拆包，并且容易获得遗传信息以进行阅读和复制。这项研究将阐明控制染色体组织的物理原理，这是生命系统物理学的一个新兴前沿。研究人员将专注于开发人类染色体的聚合物模型，并使用这些模型来阐明间期三维基因组组织的原则。最近开发的实验技术提供了丰富的信息，染色体的相互作用，并揭示了多层次的染色体组织，每一个具有其独特的物理特性：在大规模，染色体组织成交替的活性和非活性染色质隔间;在较小的规模，这些分区成子域。很少有人知道可能的物理机制，驱动这样的组织在每一个层次，以及如何连接不同的层次。现有的数据为开发和测试染色体组织的物理模型提供了极好的资源，使我们能够解决一个基本问题：DNA在人类染色体内是如何折叠的？针对新生和高中生的活动包括：（1）通过非常成功的麻省理工学院PRIMES，让高中生参与我们小组的前沿研究;（2）通过麻省理工学院本科生研究机会计划，让麻省理工学院本科生参与我们提议的研究;（3）开发新的新生定量生物学研讨会，旨在培养下一代麻省理工学院的学生欣赏和理解物理学在生命系统中的作用。PI将解决许多重要的和未探索的问题，例如解凝聚时出现的非平衡态的性质、拓扑约束的作用以及多尺度结构形成中杂聚物相互作用的影响。该项目的四个具体目标是：（1）开发一个聚合物系综的非平衡模型，以表征有丝分裂后解凝聚的整个染色体;（2）确定可导致人类染色体组织成大（1- 5 Mb）区室的物理机制和杂聚物相互作用;（3）在较小的范围内开发领域组织模型（0.2- 1 Mb）水平，并阐明可以作为这种组织基础的杂聚物特征;（4）开发一个多尺度模型，该模型整合了这三个层次的组织，并且可以解释Hi-C和显微镜数据的几个特征和特性。