CAREER: Physics of Chromatin: Micromechanics of Active Chromatin Dynamics in Interphase

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The DNA molecule in our cells is wrapped in a structure known as chromatin. Understanding how chromatin changes in time presents a fundamental question and is currently a frontier in both polymer physics as well as cell biology. To a physicist, chromatin is an exquisite example of a confined polymer that is subject to the basic laws of physics. To a biologist, chromatin controls gene expression, and physically packages DNA in a way that facilitates its replication and segregation. This project will lead to a mechanistic picture of active chromatin dynamics in live cells by integrating quantitative experimental approaches and theory from different areas of physics. As a part of this research program, the PI will develop a science outreach component targeting high school girls from underrepresented groups. In addition, this research program will provide training opportunities for undergraduate and graduate students, who will be trained in advanced optical microscopy techniques, small angle X-ray scattering, image processing, data analysis and polymer physics and statistical mechanics approaches pertinent to active systems far from equilibrium.The sequence of the human genome has been known for two decades, but its dynamic organization in three dimensions remains elusive. Methods like fluorescence in situ hybridization (FISH) or chromosome conformation capture (HiC) provided insights into how the chromatin is organized inside the cell nucleus. Methods like chromatin immunoprecipitation combined with sequencing (ChIP-Seq) helped us to map specific molecular players to the specific genomic loci within the context of specifics functions, usually transcriptional regulation. While FISH and HiC methods give us a 3D picture of the genome organization, it is a static picture, i.e. a snapshot of the human genome in a given time; they do not inform on the dynamic reorganization of the genome inside the nucleus. Similarly, Chip-Seq provides us with a snapshot of detailed 1D localization information of proteins of interest. The missing link in our current understanding is the connection between the 1D genomic information and the 3D topology of the cell nucleus in real time. The overall goal of this research program is to generate this missing link, i.e. to develop a real-time imaging of spatiotemporal dynamics of the human genome and understand the underlying physical laws. This research focuses on elucidating physics underlying nonequilibrium soft matter. Specifically, it presents development of an experimental and intellectual framework for understanding the dynamic behavior of chromatin in live cells. Chromatin presents an active polymer living in a confinement of the cell nucleus that is very different from the soft matter traditionally studied. It undergoes dynamic rearrangements, dissipates energy and exhibits self-organization far from thermodynamic equilibrium. Understanding of the mechanism/s beyond the active dynamics and elucidating the physical laws that such dynamics follows, will teach us new physics and its role in nuclear physiology.This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Cellular Cluster in the Division of Molecular and Cellular Biosciences.