SWI/SNF and the histone chaperone Rtt106 drive expression of the Pleiotropic Drug Resistance network genes.
SWI/SNF and the histone chaperone Rtt106 drive expression of the Pleiotropic Drug Resistance network genes.
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SWI/SNF 和组蛋白伴侣 Rtt106 驱动多效性耐药网络基因的表达。
DOI：
10.1038/s41467-022-29591-z
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发表时间：
2022-04-12
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
多效性耐药(PDR)网络是真菌药物反应的中心，其过度激活与耐药有关。然而，对PDR网络的基因调控还不是很清楚。在这里，我们证明了组蛋白伴侣Rtt106和染色质重构体SWI/SNF控制着PDR网络基因的表达并赋予耐药性。在酿酒酵母中，Rtt106特异性地定位于依赖于转录因子Pdr3的PDR网络基因启动子，而不是Pdr1，对于Pdr3介导的PDR网络基因的基础表达是必不可少的，而SWI/SNF对于基础表达和药物诱导的表达都是必不可少的。同样在致病真菌光滑假丝酵母中，Rtt106和SWI/SNF调节药物诱导的PDR基因表达。一直以来，Rtt106或SWI/SNF的缺失使耐药的酿酒酵母突变株和光滑葡萄球菌对抗真菌药物敏感。由于它们协同驱动PDR网络基因的表达，Rtt106和SWI/SNF是对抗真菌耐药性的潜在治疗靶点。多效性耐药(PDR)网络是真菌药物反应的中心，其过度激活与耐药有关。在这里，作者表明染色质重构体SWI/SnF和组蛋白伴侣Rtt106对于真菌中PDR基因的表达是重要的，因此介导了对抗真菌药物的耐药性。
The Pleiotropic Drug Resistance (PDR) network is central to the drug response in fungi, and its overactivation is associated with drug resistance. However, gene regulation of the PDR network is not well understood. Here, we show that the histone chaperone Rtt106 and the chromatin remodeller SWI/SNF control expression of the PDR network genes and confer drug resistance. In Saccharomyces cerevisiae, Rtt106 specifically localises to PDR network gene promoters dependent on transcription factor Pdr3, but not Pdr1, and is essential for Pdr3-mediated basal expression of the PDR network genes, while SWI/SNF is essential for both basal and drug-induced expression. Also in the pathogenic fungus Candida glabrata, Rtt106 and SWI/SNF regulate drug-induced PDR gene expression. Consistently, loss of Rtt106 or SWI/SNF sensitises drug-resistant S. cerevisiae mutants and C. glabrata to antifungal drugs. Since they cooperatively drive PDR network gene expression, Rtt106 and SWI/SNF represent potential therapeutic targets to combat antifungal resistance. The Pleiotropic Drug Resistance (PDR) network is central to drug response in fungi, and its overactivation is associated with drug resistance. Here the authors show that the chromatin remodeller SWI/SNF and the histone chaperone Rtt106 are important for PDR gene expression in fungi and therefore mediate resistance to antifungal drugs.
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