Physics of 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.