Role of chromosome in organizing space and time inside cells

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The largest biomolecule, genomic DNA, folds into a structure whose physical properties organize both space and time within a cell. My interdisciplinary research program applies methods from statistical physics to uncover the constraints that influence DNA structure and how that structure impacts function. We will pursue three directions of research. 1) Within a cell, DNA folds into chromatin that is shaped by the interactions of DNA-bound protein "factors" that aid loop formation. This looping also influences where factors bind, creating feedback. This unique aspect of the chromatin-folding problem is not present in the folding of other biomolecules like RNA and proteins where the interactions are fixed by the sequence alone. Current methods that aim to solve the chromatin-folding problem lack this self-consistency. We will develop a model that can self-consistently predict both DNA structure and the distribution of bound factors. Our models will be tested experimentally by our collaborator, Olivier Cuvier (CNRS) whose lab studies chromatin regulation. 2) A key cellular process that depends on the folding of DNA is transcription. It is regulated by proteins known as transcription factors (TFs) that bind sequences known as enhancers, which regulate the binding of RNA-polymerase that reads out genes. Recent experiments can measure the function of enhancers on a genome-wide scale, providing unprecedented data to decipher the regulatory logic of TFs. Current methods of analyzing this data are based on deep-learning, which does not provide clear mechanistic insight. Using Bayesian methods, we will infer a predictive biophysical model of enhancer function that can provide information about the interactions among TFs, RNA-polymerase and structure. Nathan Lack's Lab (Vancouver Prostate Centre) has measured a large library of enhancers involved in hormone signaling, and we will use our method to reveal the regulatory logic of this pathway. At a broader level, we expect our work on folding and transcription to highlight the necessity of modeling chromatin and the processes that depend on it in a self-consistent way. 3) Lastly, the DNA polymer can drive spatial organization in a cell. The segregation of genetic material in some bacteria is an active process governed by a two-protein system that is thought to exploit the entropic elasticity of DNA to drive motion. Its efficiency has yet to be characterized in either experiment or simulation. Recent experimental work has also called into question whether the entropic force of DNA is sufficient to segregate whole chromosomes. We will develop a mechano-chemical model for this two-protein system to explore these important unanswered questions. Our collaborators in the Nancy Forde group (SFU) will then synthesize in vitro molecular-motor systems based on similar principles, and we expect our models will help elucidate the operational principles that drive motion, both in vivo and in vitro.