EFRI CEE: Epigenomic Regulation Over Multiple Length Scales: Understanding Chromatin Modifications Through Label Free Imaging and Multi-Scale Modeling

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This project will develop novel computational and imaging technologies for a new level of understanding about chromatin organization. Chromatin is the condensed complex of DNA and proteins in every cell nucleus whose structure and function is a core determinant of gene expression, and as such controls every aspect of the growth, development and health of organisms. The computational work will be used to inform experimental imaging and the imaging will correspondingly inform the computation to develop validated models of chromatin structure at multiple length scales. These models will enable scientists to address key questions about how local changes in DNA at the atomic scale relate to changes in chromatin at the nanometer scale, and ultimately alter gene expression. The new technologies developed will be made publicly available, which will facilitate research across disciplines spanning physics and engineering to biology, and support the National Science Foundation's goal of Understanding the Rules of Life. The project will involve multiple cross-disciplinary teams of graduate students and postdoctoral scholars who will be trained for successful careers in science and engineering. A 6-week summer course is also planned to inspire and train high school students for the STEM workforce.The project will start by examining the single chromatin fiber problem through exploitation of the "heat shock response" that enables cells to survive high temperatures through activation of heat shock genes. This fundamental process can be used to detect changes in chromatin structure associated with changes in gene expression. Through state-of-the-art imaging, relying on spectroscopic intrinsic-contrast photon-localization optical nanoscopy (SICLON), this work seeks to resolve chromatin structure in vivo to as low as 5 nm length scale. To extract the dynamics of chromatin in this region, computer representations of the images will be generated through combined machine learning, evolutionary optimization strategies and finite difference time domain methods. The workflow will iteratively solve chromatin configurations and infer molecular events for any epigenetic response. The project will build upon a recently developed multiscale chromatin model ideally suited for molecular-based interpretation of experimental observations. As a secondary effort, the project will scale up systems for identifying structural effects of heterochromatin domains by investigating the impact of methyltransferase activity on these domains. Again, this aspect of the work will rely on further development of label-free imaging technologies to achieve sub-10 nm resolution, with the overall goal of quantitative and predictive understanding the 3D organization of chromatin in the cell.This award is co-funded by the Genetic Mechanisms Cluster in the Division of Molecular and Cellular Biosciences in the Biological 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.