Collaborative Research: Modeling the Coupling of Epigenetic and Transcriptional Regulation

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Cells sharing the same genome exhibit different phenotypes. For the development and health of the body, cells in various tissues need to faithfully maintain their functional properties and meanwhile make necessary changes responding to environmental cues. That is, cells need to be phenotypically stable and plastic. Cells achieve this demand through proper regulation of gene expression, transcriptionally and epigenetically. Gene regulation at the transcriptional level via transcription factors has been well studied. Gene regulation at the epigenetic level via chromatin modifications has been extensively researched recently. Yet, the quantitative nature of epigenetic regulation remains largely elusive, and little is known about the coupled effects of epigenetic and transcriptional regulations. This project will develop a mathematical framework for epigenetic regulation as well as coupled epigenetic and transcriptional regulations. By combining modeling and quantitative experimental measurements, this research will address the fundamental question of cell phenotype stability and plasticity. This collaborative project will provide unique opportunities for graduate and undergraduate students to work at the interface of mathematical, physical, and life sciences. Through a summer internship program, high school students will have opportunities to experience integrated modeling/experimental research, which will encourage them to explore their interests in pursuing cross-disciplinary research careers in the future.Rapidly accumulating evidence has revealed the critical role of epigenetic regulation of gene expression. Epigenetic modifications refer to stable and inheritable changes of gene expression caused by non-genetic chromatin modifications. However, the quantitative properties of epigenetic regulation, and the coupled effects of epigenetic and transcriptional regulation on gene expression, are poorly understood. In this project, the investigators will first develop a theoretical framework describing epigenetic and transcriptional regulations of gene expression, and analyze how epigenetic dynamics and gene transcription are coupled to control stable and plastic gene activities. Investigators will then focus on a case study, the coupled epigenetic/transcriptional regulation of the Rb-E2F pathway that controls the transition between two distinct cell fates, cellular quiescence and proliferation. Guided by modeling analysis, investigators will experimentally determine the highly needed but unresolved function form for the coupling between epigenetic modification and gene transcription. By integrating approaches across statistical and chemical physics, nonlinear dynamics, and experimental biology, this project will advance our understanding of gene expression stability and flexibility via coupled transcriptional and epigenetic mechanisms, and correspondingly, of cell fate maintenance and transition between quiescence and proliferation.