URoL: Epigenetics 2: Learning the rules of dynamic epigenetic regulation

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In the nucleus of a eukaryotic cell, the DNA genome can be chemically modified to confer additional, so-called epigenetic, coding information. A central unanswered question in regulatory biology is how epigenetic information is decoded and used by cells as they grow and differentiate. This project aims to address that question by first developing experimental and computational strategies to predict how the genome and its epigenetic modifications are used and then testing the validity of the predictions. The testing will be done through experiments in simple cellular systems, as well as in cells programmed to differentiate into components of the human immune system. The results are expected to reveal regulatory ‘rules’ that can be used to engineer desirable cellular outcomes. The project will have educational impact by partnering with an existing program (Rainier Scholars, www.rainiercholars.org) to broaden participation in STEM by offering a pathway to college graduation for low-income students of color. In addition, research results from this project will be incorporated in development of course modules to teach design principles of epigenetic regulation at both participating institutions, the University of Washington and California Institute of Technology. Epigenetic regulation is central to all aspects of human biology. However, despite its centrality and the wealth of molecular information already collected, we still lack a predictive understanding of epigenetic control. This project combines synthetic biology, developmental biology, and computational machine learning approaches, to develop and validate predictive models of how chromatin state, sequence context, and specific regulators together establish gene expression state. These models will provide three key benefits. First, they will provide fundamental biological insight into the architecture of eukaryotic gene regulation. Second, they will permit engineering of synthetic chromatin-based regulatory systems that provide useful functionality, including the ability to establish stable gene expression states. Such synthetic systems would enable cell-based therapies that utilize the machinery of chromatin regulation to establish, maintain, and change cellular states in response to environmental conditions, even in cells participating in immune responses and other complex processes. Third, these models will help researchers understand how eukaryotic organisms harness chromatin regulation to control cell state transitions in their development. This knowledge not only will enhance the ability to interface with the natural cell fate control circuitry, but also will reveal design principles for optimizing the function of synthetic chromatin regulatory systems.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.