Cross-regulation among disparate antibiotic biosynthetic pathways of Streptomyces coelicolor

A complex programme of regulation governs gene expression during development of the morphologically and biochemically complex eubacterial genus Streptomyces. Earlier work has suggested a model in which 'higher level' pleiotropic regulators activate 'pathway-specific' regulators located within chromosomal gene clusters encoding biosynthesis of individual antibiotics. We used mutational analysis and adventitious overexpression of key Streptomyces coelicolor regulators to investigate functional interactions among them. We report here that cluster-situated regulators (CSRs) thought to be pathway-specific can also control other antibiotic biosynthetic gene clusters, and thus have pleiotropic actions. Surprisingly, we also find that CSRs exhibit growth-phase-dependent control over afsR2/afsS, a 'higher level' pleiotropic regulatory locus not located within any of the chromosomal gene clusters it targets, and further demonstrate that cross-regulation by CSRs is modulated globally and differentially during the S. coelicolor growth cycle by the RNaseIII homologue AbsB. Our results, which reveal a network of functional interactions among regulators that govern production of antibiotics and other secondary metabolites in S. coelicolor, suggest that revision of the currently prevalent view of higher-level versus pathway-specific regulation of secondary metabolism in Streptomyces species is warranted. Groups of assays that are related as part of a time series. Keywords: time_series_design Computed

在形态与生化特性均极为复杂的链霉菌属（Streptomyces）的发育过程中，一套复杂的调控程序掌控着基因表达。既往研究提出了一类调控模型：所谓“高层次”多效调节因子，可激活位于染色体抗生素生物合成基因簇内的“途径特异性”调节因子，这些基因簇负责编码单一抗生素的生物合成。本研究通过突变分析以及对关键天蓝色链霉菌（Streptomyces coelicolor）调节因子的异位过表达，探究了这类调节因子之间的功能互作关系。本文报道：此前被认为仅具有途径特异性的簇定位调节因子（cluster-situated regulators，CSRs），实际上亦可调控其他抗生素生物合成基因簇，因此这类调节因子本身具备多效性功能。令人意外的是，本研究还发现CSRs可对afsR2/afsS实施生长阶段依赖性调控——该位点属于“高层次”多效调节基因座，并不处于其调控的任一染色体基因簇内；进一步研究表明，在天蓝色链霉菌的生长周期中，CSRs之间的交叉调控会被核糖核酸酶III同源蛋白AbsB进行全局性且具有差异性的调控。本研究揭示了天蓝色链霉菌中调控抗生素及其他次级代谢产物合成的调节因子间的功能互作网络，这提示学界亟需修正当前对于链霉菌属次级代谢“高层次-途径特异性”调控模式的主流认知。包含按时间序列关联的多组实验。关键词：time_series_design Computed