The dynamic transcriptional and translational landscape of the model antibiotic producer Streptomyces coelicolor A3(2)

Abstract

Individual Streptomyces species have the genetic potential to produce a diverse array of natural products of commercial, medical and veterinary interest. However, these products are often not detectable under laboratory culture conditions. To harness their full biosynthetic potential, it is important to develop a detailed understanding of the regulatory networks that orchestrate their metabolism. Here we integrate nucleotide resolution genome-scale measurements of the transcriptome and translatome of Streptomyces coelicolor, the model antibiotic-producing actinomycete. Our systematic study determines 3,570 transcription start sites and identifies 230 small RNAs and a considerable proportion (∼21%) of leaderless mRNAs; this enables deduction of genome-wide promoter architecture. Ribosome profiling reveals that the translation efficiency of secondary metabolic genes is negatively correlated with transcription and that several key antibiotic regulatory genes are translationally induced at transition growth phase. These findings might facilitate the design of new approaches to antibiotic discovery and development.

Metabolic Engineering of Microorganisms for the Production of Natural Compounds

“…For example, even well characterized Streptomyces species display complex gene expression profiles depending on culture conditions, because they have complex sigma factors and elaborate gene expression control systems. [176] Also, a significant proportion of bacteria which potentially are capable of producing valuable polyketides are noncultivable in laboratory conditions. This severely has discouraged the identification and the commercialization of important novel polyketides.…”

Recent advances in understanding Streptomyces

“…Through the use of RNA sequencing to analyse the global transcription profile, and ribosome profiling (ribo-seq) to analyse translation, a near-comprehensive gene expression picture of S. coelicolor at different stages of growth in liquid culture has been obtained 122 . This survey identified most of the transcription start sites in the entire genome, including those for 230 small RNAs.…”

Omics-based natural product discovery and the lexicon of genome mining

“…Microarrays also revealed that 12 of 18 BGCs were expressed in wild-type Myxococcus xanthus , thus suggesting that many orphan BGCs may not be transcriptionally silent[31]. More recently, next-generation sequencing was employed in the global transcriptome analysis of S. coelicolor [32]. This study provided important new insight into the relationships between transcription and translation, something that remains poorly understood in the context of NP biosynthesis.…”

“…Furthermore, translation efficiencies can vary and thus expression alone is unlikely to be an adequate predictor of protein or NP production. For example, a recent study in S. coelicolor revealed that the transcription of several BGCs increased throughout growth yet their translation efficiency decreased at certain times[32]. It is also interesting to consider how the abundance of various tRNAs can affect translation efficiencies[36] and how a mutation in bldA , which is predicted to encode a misfolded Leu-tRNA molecule, can have a profound effect on BGC expression[37].…”