EFRI CEE : Engineering Technologies to Determine Causal Relationships Between Chromatin Structure and Gene Regulation

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The structure of the human genome inside of a living cell is precisely and dynamically controlled to determine the level of each gene in different cell types, in response to environmental stimuli, and in various disease conditions. The chemical modification and three-dimensional folding of our DNA plays an even greater role than our inherited genetics in human development, disease progression, and drug response. There have been tremendous advances in mapping genome sequence and structure but our understanding of the relationship between genome structure and function is relatively poor. The objective of this proposal is to cross interdisciplinary boundaries to develop the necessary technologies to accurately predict, quantitatively monitor, and deterministically program genome structure to generate improved disease models that will catalyze transformative drug development. The team will also develop educational programs to inspire the next generation of scientists in this emerging discipline.Innovative new technologies, including reporters of dynamic molecular structure and CRISPR/Cas9-based epigenome editing, provide a unique opportunity to monitor and perturb epigenetic states that govern chromatin structure. The team will generate new molecular tools for monitoring changes to epigenetic states in live cells using FRET-based nanosensors that report on structural changes to chromatin structure and mechanics in response to targeted perturbations by CRISPR/Cas9-based epigenome editing. This data will inform molecular models that predict the effect of epigenetic changes on chromatin structure and consequent changes in gene expression. These technologies and models will be validated in the context of human tumor models to illuminate the relationship between chromatin structure and cancer progression. Collectively, this will enable the development of new technologies and models that are broadly useful for disease modeling and drug screening.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.