Interactions between the transcription factors FfmA and AtrR are required to properly regulate gene expression in the fungus Aspergillus fumigatus.
Interactions between the transcription factors FfmA and AtrR are required to properly regulate gene expression in the fungus Aspergillus fumigatus.
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转录因子 FfmA 和 AtrR 之间的相互作用是正确调节真菌烟曲霉基因表达所必需的。
DOI：
10.1093/g3journal/jkad173
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发表时间：
2023-09-30
影响因子：
2.6
通讯作者：
Moye-Rowley, W. Scott
中科院分区：
文献类型：
--
作者：
Paul, Sanjoy;Stamnes, Mark A.;Moye-Rowley, W. Scott
丝状真菌烟曲霉中唑类耐药性的转录调控是这种有问题的临床表型发展的关键步骤。我们和其他人以前描述了一种含C2H2的转录因子，称为FfmA，是伏立康唑敏感性正常水平所必需的。即使在没有任何外部应力的情况下，ffmA的等位基因也表现出强烈受损的生长速率。在这里，我们采用了一种急性阻遏的多西环素关闭形式的ffmA，以迅速耗尽FfmA蛋白从细胞。使用这种方法，我们进行了RNA-seq分析以探测急性剥夺FfmA的转录组细胞。在FfmA急性消耗后，总共2，000个基因差异表达，说明了该因子的广泛转录组学效应。有趣的是，在这种FfmA表达的急性耗竭后观察到的转录组变化仅与其他人分析的ffmA Δ无效菌株中发现的那些有有限的重叠。染色质免疫沉淀结合高通量DNA测序分析（ChIP-seq）鉴定了530个与FfmA结合的基因。这些基因中有300多个也被AtrR结合，AtrR是一种在唑类药物耐药性中很重要的转录因子，表明与FfmA有显著的调控重叠。然而，虽然AtrR是一种具有已知特异性的上游活化蛋白，但我们的数据表明FfmA是一种染色质相关因子，其以依赖于其他因子的方式结合DNA。我们提供的证据表明，AtrR和FfmA在细胞中相互作用，并表现出相互的表达调节。AtrR和FfmA的相互作用是A.烟熏。 烟曲霉FfmA是一种C2H2转录因子，在全球范围内控制近20%的基因组表达。Paul等人使用ChIP-seq、蛋白质印迹和共免疫沉淀分析显示，FfmA与转录因子AtrR广泛相互作用以控制唑类药物抗性。作者的数据表明，FfmA是一种染色质相关蛋白，通过与AtrR和其他因子的相互作用被招募到DNA中。
Transcriptional regulation of azole resistance in the filamentous fungus Aspergillus fumigatus is a key step in development of this problematic clinical phenotype. We and others have previously described a C2H2-containing transcription factor called FfmA that is required for normal levels of voriconazole susceptibility. Null alleles of ffmA exhibit a strongly compromised growth rate even in the absence of any external stress. Here, we employ an acutely repressible doxycycline-off form of ffmA to rapidly deplete FfmA protein from the cell. Using this approach, we carried out RNA-seq analyses to probe the transcriptome cells acutely deprived of FfmA. A total of 2,000 genes were differentially expressed upon acute depletion of FfmA, illustrating the broad transcriptomic effect of this factor. Interestingly, the transcriptome changes observed upon this acute depletion of FfmA expression only shared limited overlap with those found in an ffmAΔ null strain analyzed by others. Chromatin immunoprecipitation coupled with high throughput DNA sequencing analysis (ChIP-seq) identified 530 genes that were bound by FfmA. More than 300 of these genes were also bound by AtrR, a transcription factor important in azole drug resistance, demonstrating striking regulatory overlap with FfmA. However, while AtrR is an upstream activation protein with known specificity, our data suggest that FfmA is a chromatin-associated factor that binds DNA in a manner dependent on other factors. We provide evidence that AtrR and FfmA interact in the cell and show reciprocal expression modulation. Interaction of AtrR and FfmA is required for normal gene expression in A. fumigatus. Aspergillus fumigatus FfmA is a C2H2 transcription factor that acts globally to control expression of nearly 20% of the genome. Paul et al. show using ChIP-seq, western blot and co-immunoprecipitation analyses that FfmA extensively interacts with the transcription factor AtrR to control azole drug resistance. The authors’ data argue that FfmA is a chromatin-associated protein that is recruited to DNA via interaction with AtrR and other factors.
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