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

果蝇中Keap1-Nrf2异种反应信号对染色质的表观遗传调控

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.