组蛋白乙酰转移酶Elp3调控烟曲霉毒力的分子机制研究

深入了解烟曲霉的毒力因子是有效治疗烟曲霉感染的关键。已有证据显示组蛋白乙酰化修饰与动植物病原菌的毒力密切相关，但不同物种间乙酰化修饰的调控机制差异较大。目前对于人类重要条件致病真菌烟曲霉中组蛋白乙酰化修饰的功能还知之甚少。本项目前期运用信息学分析预测出烟曲霉中存在13个编码组蛋白乙酰转移酶的基因，通过大蜡螟模型毒力筛选，发现组蛋白乙酰转移酶Elp3的缺失几乎不影响烟曲霉生长但毒力显著降低。拟进一步通过位点突变、体内外酶活检测、小鼠毒力模型，研究烟曲霉组蛋白乙酰转移酶Elp3的生物学功能。并结合RNA-seq、ChIP-qPCR、乙酰化蛋白质组学等手段，探究Elp3的转录调控途径和靶点蛋白，进而从基因转录和蛋白翻译后修饰两个层面解析具体分子机制和调控网络，最终系统地阐明组蛋白乙酰转移酶Elp3与烟曲霉毒力的关系，为深入认识组蛋白乙酰化修饰调控烟曲霉乃至病原真菌毒力的作用机制奠定理论基础。

An in-depth understanding of the virulence determinants of Aspergillus fumigatus is the crucial for the treatment of A. fumigatus infection. There is emerging evidence that histone acetylation plays an important role in the virulence of animal and plant pathogens, but the underlying mechanisms among different species are quite distinct. In human opportunistic pathogen A. fumigatus, functions of histone acetylation are yet to be characterized. In this project, we previously identified thirteen genes which encode putative histone acetyltransferases (HATs) in A. fumigatus using bioinformatics analysis. To determine whether HATs affecting A. fumigatus virulence, we employed the Galleria mellonella infection model to screen all thirteen full-deletion mutants of HAT genes. Surprisingly, among these mutants, the depletion of the histone acetyltransferase Elp3 showed a minor growth defect but significantly attenuated in virulence. Based on this finding, we will further investigate the biological functions of histone acetyltransferase Elp3 by site-directed mutagenesis, in vitro and in vivo enzymatic assay, and mouse model in A. fumigatus. Moreover, with the combination of RNA-seq, ChIP-qPCR, acetylation proteomics approaches, we aim to identify the putative target genes and HAT substrates regulated by Elp3, and therefore provide new insights into the regulatory mechanism of A. fumigatus Elp3 for altering gene expression and protein post-translational modification. On the basis of results from this project, we will finally systematically elucidate the relationship between the histone acetyltransferase Elp3 and the virulence of A. fumigatus and pave the fundamental way for better understanding the mechanism of histone acetylation modification regulating the virulence of A. fumigatus and other pathogenic fungi.