Theoretical Modeling of Protein-Driven Chromosomal Dynamics and Biological Function

Stanford University, Stanford CA

Investigators

Abstract

This research project aims to enhance the use of theoretical and simulation approaches to address critical biological problems that have both fundamental and practical impact. The models used in this project draw from the fields of polymer and soft-materials physics and infuse novel physical concepts and understanding into problems involving living cells and organisms. The engagement of both in vitro and in vivo experimental measurements will provide guidance on the implementation of quantitative theory into practical biological problems. Results from this program will be widely disseminated through publications, conferences, and an online repository of simulation tools as well as descriptions, press releases, and educational tools for use by the broad scientific community and the general public. The lab of the PI is an ideal environment for training quantitative biologists who are capable of tackling a diverse range of fundamental and applied problems in living systems, and the lab's commitment to diversity and educational development has led to alumni of the group who are making major contributions to both academic and industrial research. This program develops and implements laboratory science and engineering teaching modules for the education of high school students who are being treated for childhood cancer and other illnesses. This program is piloted at the Hospital School at the Lucile Packard Children's Hospital, and the PI engages undergraduate and graduate students at Stanford to develop the program, resulting in an exciting opportunity for students to enrich their educational experience with broader outreach. Ongoing efforts aim to broadly disseminate this program nationally as a general laboratory science curriculum for hospital-school education. Prokaryotic and eukaryotic cells have the daunting task of compactly packaging their immense genome while simultaneously maintaining gene regulatory control and the ability for chromosomal DNA to be replicated and segregated in a robust manner. Chromosomal DNA within living cells is manipulated and accessed by a host of proteins that perform numerous functions that are orchestrated throughout the cell cycle. The physical manipulation of chromosomal DNA is central to its function, and achieving a fundamental quantitative framework for predicting and interpreting chromosomal organization and dynamics would be instrumental to our understanding of living systems. This research program aims to tackle three major biological processes involving chromosomal DNA in prokaryotic cells: regulation, segregation, and organization. These efforts are delineated into three complementary thrusts that establish fundamental physical insight into the orchestrated function of proteins that influence chromosomal organization and dynamics. In Thrust 1, the PI addresses the impact of DNA supercoiling on gene regulation. This effort focuses on two prototypical regulatory proteins (Lac repressor and ë repressor) that serve as examples of regulatory proteins that engage DNA at multiple sites to form a regulatory complex. Cellular control of supercoiling elicits major changes in gene regulation, and this thrust will directly address how topoisomerases and regulatory proteins orchestrate their function. Thrust 2 aims to address segregation of DNA through the ParABS system's highly conserved prokaryotic segregation apparatus. The mysterious function of this system is unlike motor or cytoskeletal proteins in that there is no obvious force generating function. The efforts will aim to resolve how temporal correlations in chromosomal dynamics result in directed motion in a burning-bridge mechanism for the ParABS system. In Thrust 3, the PI will tackle the interplay between RNA polymerase and condensin in dictating chromosomal organization. Active forces generated by RNA polymerase displace proteins along DNA, and the resulting impact of these nonequilibrium processes on chromosomal organization will be addressed in this thrust, providing new physical insight into the formation and maintenance of organized domains within the cell. This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Genetic Mechanisms Cluster in the Division of Molecular and Cellular Biosciences.