Multilevel regulation of gene expression in brasilicardin biosynthetic gene cluster
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PROVIDER: PRJNA1134241 | ENA |
REPOSITORIES: ENA
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Project description:Brasilicardin A, BraA, is a secondary metabolite produced by the bacterium Nocardia terpenica, and a promising drug due to potent immunosuppressive activity and low cytotoxicity. Currently, a semisynthetic approach confers production of a complete compound but suffers from insufficient biosynthesis of BraA intermediates used in the chemical synthesis steps leading to only lab scale quantities of the compound. A better understanding of gene expression regulatory pathways within the brasilicardin biosynthetic gene cluster, Bra-BGC, is a prerequisite to further improvements in the biosynthesis titers. However, a transcriptional regulation in Bra-BGC has only been superficially analyzed, till now. In this study, we comprehensively analyze the functions of several unstudied transcriptional regulators, KstR, SdpR and OmpR, encoded within the close vicinity of the Bra-BGC, and delve the role of the previously described cluster-situated activator Bra12. We present, that the Bra12 and the novel regulator SdpR, bind several DNA sequences located in the promoter regions of the genes essential for BraA biosynthesis. Subsequently, we demonstrate complex regulatory network through which both regulators are capable of controlling activity of those gene promoters and thus gene expression in Bra-BGC. Furthermore, using heterologous producer strain Amycolatopsis japonicum, we present, that Bra12 and SdpR regulators play opposite roles in brasilicardin congeners biosynthesis in. Finally, we propose a comprehensive model of multilevel gene expression regulation in Bra-BGC and propose the roles of locally encoded transcriptional regulators
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Project description: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. Computed
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