Toxoplasma Epigenomics and Gene Expression

描述（由申请人提供）：专性细胞内寄生虫刚地弓形虫是艾滋病流行的主要机会性病原体。当它在宿主细胞内发育时，寄生虫实现了顺序基因表达的协调模式。为了应对压力和环境的变化，寄生虫完全改变了自身的代谢、表面抗原和细胞周期，从速殖体转变为慢殖体。了解弓形虫如何调节基因表达是了解弓形虫病发病机制的基础。表观遗传因素控制着弓形虫的发育转变和毒力性状的表达，也与弓形虫慢殖子的分化有关。在弓形虫中，染色质重塑复合物如何与转录机制相互作用尚不清楚。最近，一个类似植物的转录因子家族APETELA 2（或AP2）家族被发现并被认为是弓形虫和其他顶复合体的主要转录因子。我们假设保守的apiccomplexa AP2家族成员在弓形虫中作为序列特异性转录因子具有保守的功能，这些转录因子与一般转录因子和染色质重塑复合物相互作用以调节基因表达。我们之前已经开发了速殖子的表观基因组图谱，定义了基因组的功能区域。我们将利用之前的工作来帮助我们确定TgAP2调控的基因。AP2蛋白的DNA结合特异性将采用多学科方法进行鉴定。与TgAP2相互作用的蛋白将通过蛋白质组学进行鉴定。这些研究将形成一个框架，在此基础上，我们将建立系统生物学模型，以了解基因网络如何控制生物学上重要的事件，如慢殖子形成。

DESCRIPTION (provided by applicant): The obligate intracellular parasite Toxoplasma gondii is a major opportunistic pathogen of the AIDS epidemic. As it develops within host cells, the parasite implements a coordinated pattern of sequential gene expression. In response to stress and changes in its environment, the parasite completely alters its metabolism, surface antigens, and cell cycle to transition from tachyzoite to bradyzoite. Understanding how T. gondii regulates gene expression is fundamental for understanding the pathogenesis of toxoplasmosis. Epigenetic factors govern developmental transitions and expression of virulence traits, and are also implicated in T. gondii bradyzoite differentiation. How chromatin remodeling complexes interact with transcriptional machinery in T. gondii is not known. Recently, a plant-like transcription factor family, the APETELA 2 (or AP2) family, has been discovered and proposed as the primary transcription factors of T. gondii and other Apicomplexa. We hypothesize that conserved Apicomplexa AP2 family members have conserved functions in T. gondii as sequence-specific transcription factors that interact with general transcription factors and chromatin remodeling complexes to regulate gene expression. We have previously developed a epigenomic map of tachyzoites that defines functional regions of the genome. We will use this prior work to assist us in determining the genes regulated by TgAP2. The DNA binding specificity of AP2 proteins will be identified using a multidisciplinary approach. Proteins that interact with TgAP2 will be identified using proteomics. These studies will form a scaffold upon which we will build systems biology model to understand how gene networks govern biologically significant events such as bradyzoite formation.