Genetic interaction networks mediate individual statin drug response in Saccharomyces cerevisiae
Genetic interaction networks mediate individual statin drug response in Saccharomyces cerevisiae
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DOI：
10.1038/s41540-019-0112-5
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发表时间：
2019-10-03
影响因子：
4
通讯作者：
Atkinson, Paul H.
中科院分区：
文献类型：
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作者：
Busby, Bede P.;Niktab, Eliatan;Atkinson, Paul H.
真核遗传相互作用网络（GIN）在酿酒酵母S288 C模型中使用缺失文库进行了广泛描述，但仅限于这一遗传背景，无法提供个体药物反应的信息。在这里，我们在三个额外的遗传背景中创建了缺失文库。他汀类药物的反应进行了探索，对四个遗传背景的五个查询。代表药物-基因和基因-基因相互作用的20个GIN不被功能富集、层次聚类和基于拓扑的社区划分所保守。未折叠蛋白反应（UPR）社区表现出遗传背景的变化，包括不同的介数基因的网络瓶颈，我们实验验证了这个UPR社区通过测量的UPR差异激活和调节他汀类药物耐药菌株相对于他汀类药物敏感的S288 C背景。这些拓扑结构和功能的网络分析提供了深入了解遗传背景影响的药物反应的复杂性。
Eukaryotic genetic interaction networks (GINs) are extensively described in the Saccharomyces cerevisiae S288C model using deletion libraries, yet being limited to this one genetic background, not informative to individual drug response. Here we created deletion libraries in three additional genetic backgrounds. Statin response was probed with five queries against four genetic backgrounds. The 20 resultant GINs representing drug-gene and gene-gene interactions were not conserved by functional enrichment, hierarchical clustering, and topology-based community partitioning. An unfolded protein response (UPR) community exhibited genetic background variation including different betweenness genes that were network bottlenecks, and we experimentally validated this UPR community via measurements of the UPR that were differentially activated and regulated in statin-resistant strains relative to the statin-sensitive S288C background. These network analyses by topology and function provide insight into the complexity of drug response influenced by genetic background.