PDF(Pubmed)
Abstract：
Mucorales are basal fungi that opportunistically cause a potentially fatal infection known as mucormycosis (black fungus disease), which poses a significant threat to human health due to its high mortality rate and its recent association with SARS-CoV-2 infections. On the other hand, histone methylation is a regulatory mechanism with pleiotropic effects, including the virulence of several pathogenic fungi. However, the role of epigenetic changes at the histone level never has been studied in Mucorales. Here, we dissected the functional role of Set1, a histone methyltransferase that catalyzes the methylation of H3K4, which is associated with the activation of gene transcription and virulence. A comparative analysis of the Mucor lusitanicus genome (previously known as Mucor circinelloides f. lusitanicus) identified only one homolog of Set1 from Candida albicans and Saccharomyces cerevisiae that contains the typical SET domain. Knockout strains in the gene set1 lacked H3K4 monomethylation, dimethylation, and trimethylation enzymatic activities. These strains also showed a significant reduction in vegetative growth and sporulation. Additionally, set1 null strains were more sensitive to SDS, EMS, and UV light, indicating severe impairment in the repair process of the cell wall and DNA lesions and a correlation between Set1 and these processes. During pathogen-host interactions, strains lacking the set1 gene exhibited shortened polar growth within the phagosome and attenuated virulence both in vitro and in vivo. Our findings suggest that the histone methyltransferase Set1 coordinates several cell processes related to the pathogenesis of M. lusitanicus and may be an important target for future therapeutic strategies against mucormycosis.
摘要：
毛霉菌是基础真菌，机会性地引起称为毛霉菌病（黑木耳病）的潜在致命感染，由于其高死亡率以及最近与SARS-CoV-2感染的关联，对人类健康构成了重大威胁。另一方面,组蛋白甲基化是一种具有多效性的调控机制，包括几种病原真菌的毒力。然而,表观遗传变化在组蛋白水平上的作用从未在Mucorales中研究过。这里,我们剖析了Set1的功能作用，Set1是一种催化H3K4甲基化的组蛋白甲基转移酶，它与基因转录和毒力的激活有关。对Mucorlusitanicus基因组（以前称为Mucorcircinelloidesf。lusitanicus）的比较分析仅从白色念珠菌和酿酒酵母中鉴定出Set1的一个同源物，该同源物包含典型的SET结构域。基因set1中的敲除菌株缺乏H3K4单甲基化，二甲基化，和三甲基化酶活性。这些菌株还显示营养生长和孢子形成的显着减少。此外,set1空菌株对SDS更敏感，EMS,和紫外线，表明细胞壁和DNA损伤的修复过程严重受损，以及Set1与这些过程之间的相关性。在病原体-宿主相互作用期间，缺乏set1基因的菌株在吞噬体内表现出缩短的极性生长，并在体外和体内均减弱了毒力。我们的发现表明，组蛋白甲基转移酶Set1协调了与Lusitanicus发病机理相关的几个细胞过程，并且可能是未来针对毛霉菌病的治疗策略的重要靶标。
