Unravelling the γ-butyrolactone network in Streptomyces coelicolor by computational ensemble modelling

Abstract

Antibiotic production is coordinated in the Streptomyces coelicolor population through the use of diffusible signaling molecules of the γ-butyrolactone (GBL) family. The GBL regulatory system involves a small, and not completely defined two-gene network which governs a potentially bi-stable switch between the "on" and "off" states of antibiotic production. The use of this circuit as a tool for synthetic biology has been hampered by a lack of mechanistic understanding of its functionality. We here present the creation and analysis of a versatile and adaptable ensemble model of the Streptomyces GBL system (detailed information on all model mechanisms and parameters is documented in http://www.systemsbiology.ls. manchester.ac.uk/wiki/index.php/Main_Page). We use the model to explore a range of previously proposed mechanistic hypotheses, including transcriptional interference, antisense RNA interactions between the mRNAs of the two genes, and various alternative regulatory activities. Our results suggest that transcriptional interference alone is not sufficient to explain the system's behavior. Instead, antisense RNA interactions seem to be the system's driving force, combined with an aggressive scbR promoter. The computational model can be used to further challenge and refine our understanding of the system's activity and guide future experimentation.

Antifungal Activity and Biosynthetic Potential of New Streptomyces sp. MW-W600-10 Strain Isolated from Coal Mine Water

“…A number of solutions could be potentially employed to induce the expression of dormant clusters. They involve genetic manipulation of the regulatory network of the clusters [ 39 ], co-culture approaches with other microorganisms [ 38 , 84 ], and stimulations by culture supplementation [ 85 , 86 ]. Work by Colombo et al [ 87 ] has shown the influence of the culture medium on the antifungal activity of 20 Streptomyces strains against six strains of Fusarium .…”

Harnessing intercellular signals to engineer the soil microbiome

“…61–64 Similarly, Streptomyces coelicolor butyrolactones (SCBs, 8 ) act as a diffusible signal, able to relieve ScbR repression at promoters such as for cpkO , which encodes an activator for the coelimycin ( 15 ) BGC. 65–67 In Streptomyces avermitilis , the cognate GBL avenolide ( 9 ) induces production of the insecticide avermectin ( 16 ). No increase in production of avermectin was observed with SCB1, however, providing evidence of the specificity of these signals.…”

“…82 Concurrent use of multiple molecular profiling technologies represents a promising avenue to comprehensively characterise signalling in a microbiome; to effectively bring these complex datasets together to predict the emergent properties of a signalling network from genome to transcriptome to metabolome and phenotype will require the development of computational models. 83 Models have been developed for understanding signalling circuits, such as γ-butyrolactone signalling in S. coelicolor , 66 or to predict the metabolic interactions within an entire multi-species community, as demonstrated with the experimentally-validated prediction of the equilibrium of a three-species consortium with COMETS. 84 As we expand our understanding of signalling in the soil by diverse complementary methodologies, we increase our possibilities for its reverse-engineering.…”

Synthetic biology approaches to actinomycete strain improvement

“… 2018 ), are now making it possible to model additional aspects of actinomycete biology. For example, ensemble modeling has been employed for a detailed analysis of the γ-butyrolactone network in S. coelicolor (Tsigkinopoulou, Takano and Breitling 2020 ), a system with exciting potential as an engineered regulatory circuit to control secondary metabolic pathways (Biarnes-Carrera et al . 2018 ; Biarnes-Carrera, Breitling and Takano 2018 ).…”