CAREER: Chromatin Folding from the Bottom-up

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Chromatin, the seemingly inert structure that packages the DNA, plays an active role in regulating gene expression. Multiple chromatin states with distinct patterns of histone modifications and selective protein accessibility have been identified. This research will lead to a detailed structural characterization of the differences between these states to reveal the chromatin structure-function relationship and elucidate the molecular mechanisms of gene regulation. Insights from this study could inspire the design of new cancer therapeutic strategies using small molecules to target chromatin regulators and modulate chromatin structure to restore normal gene expression profiles. Technological innovations from our study will be of great interest to the more general modeling community. They can be applied to other systems with activated processes that occur over a wide range of timescales. Molecular simulation techniques used in the research, when combined with virtual reality toolsets, could produce demonstrations for a memorable and interactive learning experience. These demonstrations could inspire students’ interest in chemistry and molecular biology. They will be incorporated into an outreach program and presented to middle school and high school students in the Greater Boston area. The project aims to study the chromatin organization using a near-atomistic force field with implicit solvation. The force field's accuracy in describing protein-protein and protein-DNA interactions will be systematically improved. Using advanced sampling and free energy computation algorithms, we will compute the most probable pathways for fibril structure formation to study the dynamics and mechanism of chromatin folding. Comparing the stability between fibril structures with that of disordered configurations along the folding pathway may provide insight into the challenge of detecting the 30nm fiber in situ. The research will also investigate the impact of key protein regulators on chromatin organization by characterizing both facultative and constitutive heterochromatin. High-resolution structures for protein/chromatin complexes can elucidate how chromatin regulators mediate long-range nucleosomal contacts for histone mark propagation. They can further reveal how phase separation drives chromatin into condensed but dynamic conformations revealed in FRAP experiments. Close collaboration with experimental groups will also prove crucial for validating model accuracy and falsifying predictions. The proposed research will significantly enhance our understanding of the molecular determinants that drive chromatin folding in vitro and situ and help move chromatin modeling towards quantitative and predictive directions. This project is supported by the Molecular Biophysics and Genetic Mechanisms Clusters of the Molecular and Cellular Biosciences Division in the Directorate for Biological Sciences.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.