Collaborative Research: Interphase Chromatin as a Complex Active Fluid: Experiments and Microscopic to Mesoscopic Modeling

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Almost every human cell contains a copy of the 3-meters of genetic material (DNA) that makes us unique. In an amazing achievement, the genetic sequence of these enormous DNA molecules was decoded about twenty years ago. Despite knowing the sequence, it remains unclear how these enormous molecules are packed into a cell nucleus (approximately a six micrometer diameter sphere) in a way that the genetic information can be useful. Understanding how the information in DNA is made available for use by the cell is fundamental for advances in modern medicine and to advancing health. During one phase in the growth of cells, the molecules of the nucleus fill it in an uncondensed polymeric form that rapidly moves because of natural thermal agitation. The molecular motion is not fully understood, especially the coherent motions caused by the close packing in the nucleus where many parts of the molecules move together. The goal of this research is to determine the mechanisms of this dynamic self-organization using a powerful combination of experiments, simulations and modeling. By providing a microscopic description for the origin of coherent motions, the proposed research will transform our understanding of the mechanobiology of the nucleus. This project also will provide novel educational opportunities for graduate and undergraduate students, who will receive training in advanced imaging techniques and analysis, cellular biology, polymer dynamics, fluid mechanics, as well as mathematical and computational modeling. This collaborative project will combine high-resolution live cell imaging experiments with theoretical and computational models to probe and illuminate the microscopic origins of interphase chromatin dynamics and its effect on the spatiotemporal self-organization of DNA. To develop a close connection between experiments and models, we will perform experiments in several cell lines with different spatial distributions of chromatin. These experiments will provide exquisite measurements of correlated motions over a wide range of length and time scales, and will be used to decipher the contributions of internal active forces on chromatin organization. Moreover, these experiments will guide theoretical and computational models based on coarse-grained descriptions of the chromatin as a confined and hydrodynamically interacting flexible polymer chain driven internally by stochastic force dipoles representing active enzymes. We will test the hypothesis that chromatin dynamics is primarily the consequence of internal activity via hydrodynamic interactions, and use quantitative comparisons between experiments and models to elucidate the symmetries, frequencies, and intensities of active events responsible for coherent motion. Such knowledge is critical for understanding the physiology of the interphase chromatin dynamics in the cell nucleus.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.