Physics of Chromosomes

23对人类染色体含有两米长的DNA。这些长DNA分子被折叠在直径约5微米的人类细胞细胞核内。染色体不仅是我们遗传信息的载体，而且是令人着迷的聚合物系统，其组织允许在细胞周期中快速打包和拆包，并易于获取遗传信息以供阅读和复制。这项研究将阐明支配染色体组织的物理原理，这是生命系统物理学中的一个新兴前沿。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理。最近发展的实验技术提供了关于染色体相互作用的丰富信息，并揭示了多个水平的染色体组织，每个水平都有其独特的物理特征：在大尺度上，染色体被组织成交替的活动和非活动染色质区段；在较小尺度上，这些染色体被划分为亚域。对于在每个级别驱动这种组织的可能的物理机制以及不同级别是如何联系的，人们知之甚少。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是如何在人类染色体内折叠的？为新生和高中生举办的活动包括：(1)通过非常成功的麻省理工学院初级课程，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)发展新的一年级数量生物学研讨会，旨在培养下一代麻省理工学院学生欣赏和理解物理在生命系统中的作用。该研讨会将讨论聚合物物理中许多重要和未探索的问题，例如解凝后出现的非平衡态的性质，拓扑约束的作用，以及杂多聚体相互作用在形成多尺度结构中的作用。该项目的四个具体目标是：(1)建立描述有丝分裂解缩后整个染色体的聚合物系综非平衡模型；(2)确定可导致人类染色体组织成大(1-5Mb)区段的物理机制和异多聚体相互作用；(3)建立较小(0.2-1Mb)水平的区域组织模型，并阐明这种组织所依据的杂多聚体的特征；(4)建立整合这三个组织水平的多尺度模型，并能够解释Hi-C和显微镜数据的几个特征和特征。

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.