Physical Mechanisms of Cell State Transitions: Size Homeostasis in Budding Yeast

Rensselaer Polytechnic Institute, Troy NY

Investigators

Abstract

In all species, cell growth and division are tightly coordinated to establish a homeostatic cell size. Size control optimizes fitness under variable environmental conditions in unicellular species, and is critical for proper organ development and maintenance in multi-cellular organisms. In humans, disruption of the networks that control cell growth, division or size is linked to many diseases, including cancer, metabolic syndrome, and cardiomyopathy. In budding yeast, size is modulated by nutrients. Cells grow fast and are large in rich nutrients and slowly and are small in poor nutrients. The PI will use a unique combination of state-of-the-art quantitative imaging methods, genetic manipulation, and mathematical modeling to construct a systems-level framework for cell size homeostasis in budding yeast. These studies will answer the longstanding question: How do cells know when they are big enough to divide? Application of the approach proposed here to other important cell state transitions will provide the foundation for the development in the private sector of new products or processes for in-tissue engineering and drug discovery. The proposed project provides highly interdisciplinary graduate training in biology, genetic engineering, physics, computation and mathematics. The Royer group hosts a large number of undergraduate students as part of the CBIS Undergraduate Research Program, the BCBP Summer internship program for predominantly minority institutions and the CBIS High School Scholars Program. Students participating in these programs will experience a "real life" application of their knowledge. The uniquely broad set of skills implicated in the research will help to prepare them for the increasingly interdisciplinary word of science and technology. The PI as Director of the RPI Graduate Program in Biochemistry and Biophysics will organize outreach to four-year colleges in the Northeast and to the public annually during Biophysics week. The hypothesis is that the transcription factors which activate the G1/S regulon leading to commitment to division, differentially and dynamically integrate nutrient signals to coordinate growth and division, thereby enabling adaptive nutrient modulation of cell size. This project has three specific objectives: i) Map the G1/S transcriptional activator nuclear organization at super-resolution as a function of size and nutrients, ii) Measure and model nutrient dependent Start dynamics, and iii) Define the upstream signaling pathways and targets for nutrient modulation of cell size. Despite the identification of literally hundreds of genes implicated in size control in budding yeast, it remains a mystery how this complex genetic network impacts the Start machinery to control size. The PI will move beyond the qualitative genetic characterization of the size control network to a quantitative understanding of how this network dynamically processes information. The strategy that will be used by the PI will provide a comprehensive, quantitative assessment of a complex biological state transition, commitment to division. The measurements of Start factor concentration and super-resolution localization will identify the key parameters for nutrient control of cell size. The mathematical models will serve as a conceptual framework for testing hypotheses, and will inform physical principles of cell division in higher organisms, including humans. Finally, the results will reveal the impact of cell-to-cell heterogeneity, or biological noise, on cell growth and the dynamics of commitment to division and size homeostasis. This work will provide the foundation for a rigorous understanding of how evolution has shaped molecular networks to cope with a stochastic environment and how robust cellular decision-making is established. This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Cellular Dynamics and Function as well as the Systems and Synthetic Biology Programs in the Division of Molecular and Cellular Biosciences. 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.