Toxoplasma Epigenomics and Gene Expression

描述（由申请人提供）：专性细胞内寄生虫弓形虫是艾滋病流行的主要机会致病菌。当它在宿主细胞内发育时，寄生虫实现了连续基因表达的协调模式。为了应对压力和环境的变化，寄生虫完全改变其代谢，表面抗原和细胞周期，从速殖子过渡到缓殖子。了解T。弓形虫对基因表达的调控是了解弓形虫病发病机制的基础。表观遗传因素控制发育转变和毒力性状的表达，也与T。弓形虫缓殖子分化染色质重塑复合物如何与T.弓形虫是未知的。最近，一个植物样转录因子家族APETELA 2（或AP 2）家族被发现并被认为是T.弓形虫和其他顶复门。我们假设保守的Apicomplexa AP2家族成员在T.弓形虫作为序列特异性转录因子，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。我们以前已经开发了一个表观基因组图谱的速殖子，定义基因组的功能区域。我们将利用这些先前的工作来帮助我们确定TgAP 2调控的基因。将使用多学科方法鉴定AP2蛋白的DNA结合特异性。将使用蛋白质组学鉴定与TgAP 2相互作用的蛋白质。这些研究将形成一个支架，我们将在此基础上建立系统生物学模型，以了解基因网络如何控制生物学上的重要事件，如缓殖子的形成。 公共卫生相关性：弓形虫是一种寄生虫病原体，可导致免疫功能低下的人（包括艾滋病患者）发生严重疾病。这种寄生虫在受感染的细胞内经历了精心策划的发育程序，并且还可以通过改变为持久的、更顽强的缓殖子形式来对其环境的变化做出反应。这些转变涉及基因表达的紧密协调。最近，我们已经开始表征新发现的T。弓形虫基因似乎调节基因表达。这些基因，AP2家族，可能是新的药物靶点，因为它们类似于植物基因，而不是哺乳动物中的基因。这些基因在许多其他影响艾滋病患者的顶复门生物中也是保守的，如隐孢子虫。了解AP 2蛋白的功能可能会导致新的治疗方法，将预防或治疗T。艾滋病患者的弓形虫感染。

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. PUBLIC HEALTH RELEVANCE: Toxoplasma gondii is a parasitic pathogen that causes severe disease in immunocompromised individuals including people with AIDS. This parasite undergoes a carefully orchestrated developmental program within infected cells and also can respond to changes in its environment by changing into persistent, hardier bradyzoite forms. These transitions involve tight coordination of gene expression. Recently we have begun to characterize newly discovered T. gondii genes that appear to regulate gene expression. These genes, the AP2 family, may be new drug targets because they resemble plant genes rather than genes seen in mammals. The genes are also conserved in many other apicomplexan organisms that affect AIDS patients such as Cryptosporidium. Understanding the function of AP2 proteins may lead to new treatments that will prevent of treat T. gondii infection in individuals with AIDS.