白念珠菌Wor1是主控白灰形态转换的一个关键因子，该因子的缺失阻断白菌向灰菌的转换，而该因子的大量表达使细胞锁定在灰菌状态。为了研究Wor1在白灰形态转换中的调控机制，我们利用酵母双杂交系统，鉴定分析了多个Wor1相互作用蛋白，包括Orf19.3345, Orf19.3845, Orf19.6291, Orf19.5035等十多个蛋白因子，序列分析比较表明这些蛋白分别属于蛋白质修饰、DNA损伤修复应答、染色质重塑以及基因转录机器相关的调控因子。本项目研究内容包括：1、Wor1表观遗传调控网络的鉴定和建立；2、Wor1蛋白的修饰包括SUMO化、磷酸化以及乙酰化在激活白菌向灰菌转换过程的功能作用；3、Wor1调控网络在白灰形态转换相关基因转录起始中的激活机制；4、Wor1与DNA损伤应答复合物相互作用在白灰转换中的调控作用；5、Wor1介导的染色质激活和沉默在白菌和灰菌维持中的作用机制。

Candida albicans is the most frequently isolated opportunistic pathogen of humans. C. albicans can switch heritably at high frequency between several phenotypes. The ability of morphologic switching is closely related to its pathogenicity. One of the high-frequency switching systems is white-opaque switching which is related to mating. We isolated and identified Wor1 (white-opaque regulator 1) as a master regulator of white-opaque switching. WOR1 expression displayed an all-or-none pattern. The expression of WOR1 was undetectable in white cells, but it was highly induced in opaque cells, suggesting its role in white-opaque switching. Deletion of the WOR1 blocked opaque cell formation; Over-expression of the WOR1 converted all cells to stable opaque cells. Importantly, the ectopic expressed Wor1 induces the transcription of WOR1 from the WOR1 its own locus, which correlates with the switching to opaque phase. The self-sustaining feedback regulation of WOR1 transcription is necessary and sufficient to promote white-opaque switching. To elucidate the mechanism of Wor1 mediated regulatory network in white-opaque switching, we constructed LexA-Wor1 as bait to screen the genomic library of C. albicans and obtained a series of Wor1 interacting proteins, including Orf19.3345, Orf19.3845, Orf19.6291, Orf19.5035, which are involved in regulation of multiple cellular processes including protein modification, DNA damage response, chromatin remodeling and transcriptional machinery. Our aim in this research will be (1) Identification of the Wor1 mediated regulatory network; (2) Effects of Wor1 modification including sumoylation, phosphorylation and acetylation on white-opaque switching; (3) Roles of the Wor1 mediated regulatory network in transcriptional activation of white-opaque switching genes; (4) Regulation of the interplay between the Wor1 and DNA damage response complex in white-opaque switching; (5) Functional study of Wor1-mediated recruitments of chromatin remodeling complex and chromatin silencing complex in white-opaque switching. Our goal is to understand the molecular and cellular mechanisms of Wor1 mediated regulatory network in white-opaque switching of C. albicans.