Malaria HATs in Transcription Regulation

描述（由申请人提供）：疟疾的负担日益增加，部分原因是寄生虫恶性疟原虫的耐药性，需要新的治疗方法。最近在转录领域的研究已经证明了染色质在真核生物中调节基因表达的功能重要性。调节染色质结构的酶对控制基因表达有着深远的影响。在这些酶中，将乙酰基从乙酰辅酶a转移到组蛋白N端末端赖氨酸残基上的组蛋白乙酰转移酶（HATs）研究得最多。干扰组蛋白乙酰化的药物的抗寄生作用以及本研究组最近对恶性疟原虫染色质重塑因子的研究表明，动态组蛋白乙酰化是一种重要的转录调控表观遗传机制，在疟原虫的发育中起着突出的作用。因此，我们提出1)表征两个转录相关的HAT蛋白家族，2)确定它们在全球转录调控中的功能作用，3)鉴定恶性疟原虫多蛋白HAT复合物的亚基。HAT蛋白将通过分子和生化方法进行表征，它们在寄生虫发育和转录调控中的功能将通过靶向基因破坏和全基因组表达分析来确定。本研究旨在揭示控制寄生虫发育和毒力的转录调控的表观遗传机制。组蛋白乙酰化在基因调控中的重要作用，以及HAT和组蛋白去乙酰化酶作为药物靶点的巨大潜力，强调了该领域研究的重要性，这可能会导致新的抗疟疾药物。疟疾在许多国家仍然是一个主要的公共卫生问题。它最近流行率的回升部分是由于耐药性。本研究旨在描述一组调节寄生虫基因表达的酶的功能，这可能导致设计新的抗疟疾药物。

DESCRIPTION (provided by applicant): The increasing burden of malaria, in part, due to drug resistance in the parasite Plasmodium falciparum, demands new therapies. Recent research in the field of transcription has demonstrated the functional importance of chromatin in regulating gene expression in eukaryotes. Enzymes that modulate chromatin structures have a profound effect on controlling gene expression. Among these enzymes, histone acetyltransferases (HATs), which transfer the acetyl group from acetyl-CoA to the lysine residues in the N- terminal tails of histones, are the best studied. The anti-parasitic effects of drugs that disturb histone acetylation and recent studies from our group on the chromatin remodeling factors in P. falciparum demonstrated that dynamic histone acetylation is an important epigenetic mechanism of transcription regulation and plays a prominent role in development of the malaria parasite. Thus, we propose to 1) characterize two families of transcription-related HAT proteins, 2) determine their functional roles in global transcription regulation, and 3) identify the subunits of multiprotein HAT complexes in P. falciparum. HAT proteins will be characterized using molecular and biochemical approaches, and their functions in parasite development and transcription regulation will be determined by targeted gene disruption and genome-wide expression analysis. This proposed research aims to reveal the epigenetic mechanisms in transcription regulation that controls the parasite development and virulence. The fundamental importance of histone acetylation in gene regulation and the great potential of HAT and histone deacetylase as drug targets underline the significance of research in this area, which may lead to novel antimalarial drugs. Malaria is still a major public health problem in many countries. Its recent resurgence in prevalence is partially due to drug resistance. This study aims to characterize the functions of a group of enzymes that regulate parasite gene expression, which may lead to the design of novel antimalarial drugs.