The ability to design genomes towards new functions has the potential to exert a broad, positive influence on society. Built from deceptively simple four bases (A, T, C and G), DNA is packaged by association with proteins into chromatin, which helps to condense the DNA into the nucleus and to regulate the DNA output. Previous work has established the importance of several factors, including chromatin compaction, the identity and modifications of the chromatin-associated proteins, as contributors to DNA output. However, we still lack understanding of the mechanisms that will allow us to effectively design DNA and chromatin architectures towards new functions. This project will take on the challenges of discovery and synthesis to meet this need by engaging teams of scientists bridging engineering and biology. For the graduate students who participate in this project, Yale's Integrated Graduate Program in Physical and Engineering Biology will serve as a framework for training a new generation of powerful practitioners of interdisciplinary science. This project will also recruit undergraduates studying biology, engineering and physics from under-represented groups to this interdisciplinary team to participate in well-defined, yet independent, projects. Engaging these students in mentoring and leadership roles for outreach programs at the high school and middle school levels will enhance their growth and confidence as scientists, engineers and scholars, while also bringing the fundamental concepts of bio-inspired design to the broader community.

The scientific goals of this project are to define the design principles that underlie chromatin organization and to leverage the genome as a device to measure and record dynamic chromatin states. Historically, a major barrier to the quantitative and comprehensive understanding of chromatin organization is the lack of versatile, tractable systems in which to probe and interpret chromatin dynamics. This project leverages methods to combine high-resolution observations of the dynamic behavior of specific chromatin loci in individual living cells with a systems-level image and data analysis pipeline that sorts single-particle-tracking data from a population of cells into discrete diffusive states. Powerful genetic tools will be employed, in combination with modular engineering strategies, to alter key factors that influence chromatin structure, including the SMC protein complexes, cohesin and condensin, to create changes in the local epigenetic landscape. Simulations will be employed to test emerging models for the origin of topologically-associating domains, such as loop extrusion; these models will be further enhanced by accounting for both the dynamics and excluded volume of the chromatin polymer in three dimensions as well as the processes that drive loop formation. These insights will be leveraged to develop an entirely novel method to record transient chromatin conformations as "memories" in the genome itself through recombinase-based state machine designs, extending biological computing to the dynamic sampling of a cell biological state.

This award is co-funded by the Genetic Mechanisms Cluster in the Division of Molecular and Cellular Biosciences in the Biological Sciences Directorate, by the Physics of Living Systems Program in the Division of Physics in the Mathematical and Physical Sciences Directorate, and by the Emerging Frontiers in Research and Innovation Program in the Division of Emerging Frontiers and Multidisciplinary Activities in the Engineering Directorate.

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.

National Science Foundation (NSF)
Emerging Frontiers (EF)
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Karen Cone
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Yale University
New Haven
United States
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