CAREER: Predicting cell fate from cell history: theory, experiment, and outreach

University Of North Carolina At Chapel Hill, Chapel Hill NC

Investigators

Abstract

This research project will lead to a better understanding of how cells -the building blocks of all living organisms- grow, divide, and pass on traits to other cells. Just as human traits, such as height or eye color, are transmitted from parents to their offspring, cells can also show observable patterns of inheritance. The specific goal of this project is to understand how a cell's inherited traits affect its future behavior; for example, whether it will stop dividing or become a more specialized type of cell. As such, this work addresses a fundamental, unanswered question in biology that could impact multiple disciplines across the life sciences. The research goals are deeply integrated with community outreach activities designed to educate and engage a diverse group of students including underrepresented minorities. The project will produce an online game in which students from an urban elementary school will create 'family trees' for cells by tracing images of cells over time. Students will earn points for each successfully tracked cell while learning the basic principles of cell biology. In addition, the investigator will host an open competition in which local high-school students compete to develop the most accurate models of cell behavior using data sets produced by the project. Thus, this project addresses a fundamental problem in cell biology and provides opportunities both to teach underrepresented groups and to draw on their emerging interest in, and talent for, science. The overarching hypothesis of this study is that, in addition to environmental cues, an individual cell's fate is strongly influenced by the sequence of events that occurred both within that cell's own lifetime as well as during the lifetimes of its ancestor cells. This hypothesis will be pursued by developing a computational model of single-cell lifetimes and lineage relationships and applying these models to understand, in quantitative terms, how a cell's individual and family history influences its fate decisions. The project will employ fluorescence time-lapse microscopy to quantify inheritance patterns across thousands of related cells spanning multiple cellular generations. Cells will be challenged with environmental stresses or developmental signals and the fates of individual cells and their offspring will be determined. With these data in hand, mathematical models will be used to: (i) understand how the lifetimes of individual cells are regulated; (ii) quantify how single-cell traits are inherited; and (iii) determine how molecular events in a cell's history determine its fate. The project focuses on the inheritance patterns of two single-cell traits: DNA double-stranded breaks (that generally slow progression through the cell cycle); and expression of a canonical pluripotency factor, OCT4 (that generally inhibits differentiation of cells and keeps them in a pluripotent state). Quantitative predictions will be validated through targeted experimental perturbations. Successful completion of the work will lead to the development of a new theoretical framework for understanding how critical events occurring throughout a cell's history shape its functional responses. 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.