Notch信号广泛参与细胞命运决定、增殖和凋亡等生命过程。为系统揭示Notch信号调控网络，本实验室在果蝇中开展遗传筛选，发现了一个新的Notch正向调控因子stuxnet (stux)。实验基础表明，Stux可能通过调控多梳复合体PcG核心组分Pc进而调节Notch基因转录。PcG复合体是表观遗传调控的核心元件。表观遗传作为一种高度保守的基因表达调控手段，在发育和生理过程中起重要作用。由于表观遗传的上游调控机制迄今还鲜见报道，本研究将拓展表观遗传学调控网络，开启表观遗传调控研究的新思路。因此提出本项目申请，拟从以下三方面研究：Stux是否通过Pc在表观遗传层面调控Notch信号通路；Stux以何种方式调节Pc和PcG复合体的功能；Stux对Pc的调节在演化上是否保守。鉴于Notch信号及PcG在果蝇与哺乳动物中的保守性，本课题将会为Notch信号和表观遗传相关疾病提供诊断和治疗的理论基础

Notch signaling is evolutionally conserved from Drosophila to mammals. It plays critical roles in many cellular processes including cell fate determination, cell proliferation and cell death. To interrogate the upstream regulatory network of Notch signaling, we identified a highly conserved gene stuxnet (stux), utilizing ample genetic tools and well-annotated genome information available in Drosophila. Excitingly, we found that Stux may function upstream of Polycomb-Group (PcG) member Pc to regulate Notch RNA production. PcG proteins function to ensure correct deployment of developmental programs by epigenetically repressing target expression. Despite the importance, few studies have been focused on the regulation of PcG machinery itself. Here, we propose to investigate the molecular mechanism by which Stux regulates Pc to control Notch signaling. We plan to conduct developmental, cellular and biochemical studies in Drosophila as well as mammalian tissue culture system. The specific Aims are as follows:.1) Determine the relationship between Stux, Pc and Notch signaling;.2) Investigate how Stux regulates Pc protein abundance and PcG complex dynamics;.3) Examine the evolutionary conservation of Stux activity between Drosophila and Mammals...Given that Notch signaling and PcG complex are highly conserved from insect to humans, the proposed studies of the normal physiological roles of Stux on Pc in Notch signaling are anticipated to be helpful for developing novel approaches to prevent and treat Notch and epigenetics related birth defects and human diseases.