Nucleus-wide epigenetic response to DNA damage

该项目的总体目标是更好地了解细胞如何对DNA损伤做出反应。最近的证据表明，局部DNA损伤会影响整个细胞状态，但这种大规模反应的机制尚不清楚。该项目旨在研究发生在DNA损伤位点之外的染色质修饰和重组的全核变化及其对基因表达的影响。该项目将为研究生、本科生和高中生提供多学科培训机会，从单细胞对DNA损伤反应的可视化到损伤信号的全基因组观点。过去的研究重点是DNA损伤位点的染色质变化，这对于正确的DNA修复很重要。最近的数据表明，损伤信号传播到这些位点之外，并引发染色质的全核变化。该项目将利用荧光单细胞成像和整合基因组测序分析的组合来确定DNA损伤诱导的组蛋白修饰和三维染色质相互作用的改变，并解决这些变化如何影响基因表达和细胞表型。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.