Epigenetic regulation of chromatin by the Keap1-Nrf2 xenobiotic response signaling in Drosophila

Keap 1-Nrf 2异生物质反应信号对果蝇染色质的表观遗传调控 摘要 保守的氧化和外源性反应因子保护细胞免受内部或外源性物质引起的损伤。 外部毒素这些因素是如何调节对恒定环境毒素的适应的，在很大程度上还不清楚。 表观遗传修饰是调节转录长期调节的重要机制 应对环境变化的能力。了解异生物质反应与 因子和表观遗传机制将有助于阐明介导表观遗传和 发展适应环境毒素，并帮助了解环境毒素的影响， 人体健康 Keap 1-Nrf 2信号通路是氧化和外源性反应所必需的，并且与 很多疾病，尤其是癌症。在之前的R15基金的支持下，我的实验室评估了这部小说， 果蝇Keap 1和Nrf 2同源蛋白dKeap 1和CncC在调节 染色质结构和发育转录。我们发现dKeap 1和CncC可以控制两者 通过与特异性伴侣如核纤层蛋白和BNF相互作用，将核纤层蛋白与异染色质和常染色质结合。在这 更新建议，我们计划全面表征分子和生物之间的相互作用， dKeap 1/CncC和染色质重塑蛋白，包括A型和B型核纤层蛋白、肌动蛋白、BNF和JIL-1。 我们还将使用一个已建立的dKeap 1“染色质关闭”突变体来完全鉴定发育基因， 直接靶向和调节的染色质结合dKeap 1在氧化还原独立的方式。最后， 我们将检验dKeap 1和/或CncC介导对异生物质的发育适应的假设。 通过细胞核中染色质结构的表观遗传调节来调节化合物。 拟议中的研究还有望加强本科教育， 和实验室。研究目标可以分为不同的子项目，这些子项目将被引入到 本科实验课程分子生物学实验室和实验生物学，或用于支持研究生 毕业论文和本科研究在邓实验室。通过参与原创性研究， 假设，学生将获得生物医学科学的丰富研究经验。

Epigenetic regulation of chromatin by the Keap1-Nrf2 xenobiotic response signaling in Drosophila ABSTRACT Conserved oxidative and xenobiotic response factors protect cells from damages caused by internal or external toxins. How these factors mediate the adaptation to constant environmental toxins is largely unclear. Epigenetic modifications are essential mechanisms that can mediate long-term adjustments of transcription profiles in responses to environmental changes. Understanding the relationship between xenobiotic response factors and epigenetic machineries will help elucidate the molecular mechanisms that mediate epigenetic and developmental adaptations to environmental toxins and help understand the effects of environmental toxins to human health. The Keap1-Nrf2 signaling pathway is essential for oxidative and xenobiotic responses and is related with many diseases especially cancer. Supported by the previous R15 grant, my laboratory assessed the novel functions of Drosophila Keap1 and Nrf2 homologous proteins, dKeap1 and CncC, in the regulation of chromatin structure and developmental transcription. We found that dKeap1 and CncC can control both heterochromatin and euchromatin through interactions with specific partners such as lamin and NURF. In this renewal proposal, we plan to comprehensively characterize molecular and biological interactions between dKeap1/CncC and chromatin remodeling proteins including A-type and B-type lamins, actin, NURF, and JIL-1. We will also employ an established dKeap1 “chromatin-off” mutant to fully identify developmental genes that are directly targeted and regulated by the chromatin-binding dKeap1 in a redox-independent manner. Finally, we will test the hypothesis that dKeap1 and/or CncC mediate developmental adaptations to xenobiotic compounds through epigenetic regulations of chromatin architecture in the nucleus. The proposed research is also expected to strengthen undergraduate educations in both the classroom and laboratory. The research aims can be divided into various sub-projects, which will either be introduced into undergraduate lab courses Molecular Biology Lab and Experimental Biology, or be used to support graduate thesis and undergraduate research in Deng laboratory. Through participating original research driven by hypothesis, students will acquire strong research experience on biomedical sciences.