Theoretical and Computational Modeling of Supercoiling, Topology, and Active Fluctuations in Chromosomal Organization and Dynamics

This research program establishes new methods to analyze and predict chromosomal organization and dynamics in living cells. Furthermore, the foundational theoretical development in this research program is transferable to a broad range of biological processes that are driven by non-equilibrium active forces. In addition, the specific biological processes that the PI will tackle provide new fundamental insight in top phenomena that are central to our understanding of chromosomal organization and function.

Reproduction and epigenetic regulation represent two of the most critical defining features in human biology. This research program brings quantitative physical insight into the molecular origins of how we reproduce and how we establish and maintain our multi-cellular programming, providing fundamental insight and predictive tools for interpreting experimental measurements.

This research program is defined by several key deliverables that provide educational resources that impact a range of communities. The educational program includes the establishment of LABScI (Laboratory Activities for Broadened Scientific Instruction) to develop and implement laboratory science and engineering teaching modules for high school students that are being treated for childhood cancer and other illnesses.

The LABScI program engages undergraduate and graduate students to develop the teaching modules, resulting in an exciting opportunity for students to enrich their educational experience. The PI will partner with the School of Education at Stanford University to expand the LACScI program and develop educational materials that effectively integrate online education with hands-on laboratory activities.

New software development in the PI's lab aims to consolidate computational approaches in physics-based modeling, genomic and bioinformatic analysis, and data-science methods. Coupled to the software development is an effort to provide educational resources that aid the implementation of these disparate approaches. New efforts in education aim to demonstrate how to effectively integrate physics-based and data-science approaches as complementary tools for biological analysis.

The instructions for all biological processes in human cells are contained within chromosomes whose total DNA length is roughly one meter. These massive DNA polymers must be capable of organizing and rearranging in response to cell-cycle events that are central to biological function. The PIs existing theory of polymer dynamics provides a starting point for describing chromosomal behavior, but a range of distinct biophysical mechanisms contribute to the behavior in living cells that are not currently captured within the existing theoretical models.

Numerous experimental observations demonstrate that chromosomal organization and dynamics are dramatically influenced by enzymes that manipulate DNA twist and supercoiling, mitigate entanglements and knots, and contribute active biological forces. This research program will establish a theoretical and computational framework for predicting and analyzing these critical biophysical drivers of chromosomal behavior.

In establishing theory that is transferable to a broad range of biological processes, the PI will focus on the following three key cell-cycle events: pairing of homologous chromosomes during meiosis, introduction of twist and supercoiling during RNA transcription, and the establishment of chromosome territories after cell division. Within this program, the PI will tackle one of the prevailing challenges in establishing a physical framework for living systems—establishing a unified predictive theory for non-equilibrium matter.

In this effort, he will develop a new theory of active-Brownian matter that provides a clear pathway for prediction of the role of transient enzymatic fluctuations in driving biological processes. This theoretical approach reveals a prevailing concept—the time-dependent temperature—that serves as a consolidating framework for capturing non-equilibrium behavior in living bio-logical systems, and will exploit this theoretical approach in specific problems that are central to the understanding of chromosomal biophysics.

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.