Nucleus-wide epigenetic response to DNA damage

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The overarching goal of the project is to better understand how cells respond to DNA damage. Recent evidence suggests that localized DNA damage affects the cell state as a whole, but the mechanisms underlying such a large-scale response are unknown. This project aims to investigate nucleus-wide changes in chromatin modification and reorganization that occur well beyond the sites of DNA damage, and their impact on gene expression. The project will provide multidisciplinary training opportunities, ranging from visualization of single cell responses to DNA damage to genome-wide views of damage signaling, for graduate, undergraduate and high school students.Past studies have focused on chromatin changes at sites of DNA damage that are important for proper DNA repair. More recent data suggest that damage signaling spreads beyond these sites and triggers nucleus-wide changes in chromatin. This project will utilize a combination of fluorescent single-cell imaging and integrative genomic sequencing analyses to determine DNA damage-induced histone modifications and alterations in three-dimensional chromatin interactions, and address how these changes influence gene expression and cellular phenotype. The outcomes will provide new insights into epigenetic DNA damage signaling in mammalian cells.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.