Nucleus-wide epigenetic response to DNA damage

该项目的首要目标是更好地了解细胞如何应对DNA损伤。最近的证据表明，局部DNA损伤会影响整个细胞状态，但这种大规模反应背后的机制尚不清楚。该项目旨在研究染色质修饰和重组在整个细胞核范围内发生的变化，这些变化远远超出DNA损伤部位，以及它们对基因表达的影响。该项目将为研究生、本科生和高中生提供多学科的培训机会，从对DNA损伤的单细胞反应的可视化到对损伤信号的全基因组观点。过去的研究重点是DNA损伤部位的染色质变化，这对适当的DNA修复非常重要。最近的数据表明，损伤信号扩散到这些部位之外，并触发染色质的核内变化。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中的变化，并解决这些变化如何影响基因表达和细胞表型。这一结果将为哺乳动物细胞中的表观遗传DNA损伤信号提供新的见解。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.