Sah Sudisht K, Yadav Anshuman, Stahl Tyler, Hayes Jeffrey J, Bulger Michael, Rustchenko Elena
Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA.
Genomic Research Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
J Fungi (Basel). 2025 Feb 1;11(2):110. doi: 10.3390/jof11020110.
Infections by the major opportunistic pathogen of human are commonly treated with echinocandin (ECN) drugs. However, can adapt to grow in the presence of certain amounts of ECNs. Prior studies by several laboratories have defined multiple genes, as well as mechanisms involving induced aneuploidy, that can govern this. Still, the mechanisms of ECN adaptation are not fully understood. Here, we use genome-wide profiling of chromatin accessibility by ATAC-seq to determine if ECN adaptation is reflected in changes in the chromatin landscape in the absence of aneuploidy. We find that drug adaptation is coupled with multiple changes in chromatin accessibility genome-wide, which occur predominantly in gene promoter regions. Areas of increased accessibilities in promoters are enriched with the binding motifs for at least two types of transcription factors: zinc finger and basic leucine zipper. We also find that chromatin changes are often associated with differentially expressed genes including genes with functions relevant to the ECN-adapted phenotype, such as cell wall biosynthesis. Consistent with this, we find that the cell wall is remodeled in ECN-adapted mutants, with chitin up and glucan down and increased cell surface exposure. A full understanding of ECN adaptation processes is of critical importance for the prevention of clinical resistance.
人类主要机会性病原体的感染通常用棘白菌素（ECN）类药物治疗。然而，（病原体）能够适应在一定量的ECN存在的情况下生长。几个实验室之前的研究已经确定了多个基因，以及涉及诱导非整倍体的机制，这些都可以控制这种情况。尽管如此，ECN适应的机制仍未完全了解。在这里，我们通过ATAC-seq对染色质可及性进行全基因组分析，以确定在不存在非整倍体的情况下，ECN适应是否反映在染色质景观的变化中。我们发现药物适应与全基因组染色质可及性的多种变化相关联，这些变化主要发生在基因启动子区域。启动子区域可及性增加的区域富含至少两种类型转录因子的结合基序：锌指和碱性亮氨酸拉链。我们还发现染色质变化通常与差异表达基因相关，包括与ECN适应表型相关功能的基因，如细胞壁生物合成。与此一致的是，我们发现ECN适应的突变体中细胞壁发生了重塑，几丁质增加而葡聚糖减少，细胞表面暴露增加。全面了解ECN适应过程对于预防临床耐药性至关重要。
