Gene activation strategies to unlock fungal secondary metabolism and its function

解锁真菌次生代谢及其功能的基因激活策略

• 批准号: 452319713
• 负责人: Dr. Annika Jagels
• 金额: --
• 依托单位: Whitney Laboratory for Marine Bioscience
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/452319713?language=en
• 关键词: Gene; activation; strategies; unlock; fungal

Many filamentous fungi produce secondary metabolites that are believed to have decisive roles in intra- and inter-species communication, competition for resources, or defense of a symbiotic partner. Moreover, most of them bear unique chemical structures and are often privileged with potent bioactivities and therefore are of exceptional interest for drug discovery. Besides the importance of these metabolites, it is estimated that only a small fraction of fungal secondary metabolites has been identified, and for a much smaller fraction ecological functions are well-studied. Thus, the proposed research targets gene activation strategies in order to unlock biosynthetic gene clusters, which are silent under standard laboratory conditions and to access new secondary metabolites of Ascomycetes. For this purpose, varying culture conditions and epigenetic manipulation via histone methylation inhibition will be applied. Metabolomics will meet transcriptomics to rapidly identify newly expressed metabolites and to integrate corresponding gene expression of respective biosynthetic gene clusters. Since there is a tremendous potential to discover new chemical entities within selected four fungal genomes, the goal is to determine the absolute configurations of novel metabolites and to examine their biological function by leveraging a panel of assays with a focus on antimicrobial activity.

许多丝状真菌产生次生代谢物，这些代谢物被认为在物种内和物种间交流、资源竞争或共生伙伴的防御中具有决定性作用。此外，它们中的大多数具有独特的化学结构，并且通常具有有效的生物活性，因此对药物发现具有特殊的意义。除了这些代谢物的重要性之外，据估计，仅鉴定了一小部分真菌次生代谢物，并且对一小部分的生态功能进行了深入研究。因此，拟议的研究目标是基因激活策略，以解锁在标准实验室条件下沉默的生物合成基因簇，并获得子囊菌的新次级代谢产物。为此，将应用不同的培养条件和通过组蛋白甲基化抑制进行的表观遗传操作。代谢组学将与转录组学结合，快速识别新表达的代谢物，并整合各个生物合成基因簇的相应基因表达。由于在选定的四种真菌基因组中发现新化学实体的潜力巨大，因此我们的目标是确定新代谢物的绝对构型，并通过利用一组以抗菌活性为重点的测定来检查其生物功能。