Overexpression of Scr1 protein induces strong changes in the transcriptome and metabolome of Streptomyces coelicolor that affect antibiotic production.

Background: Xenobiotic response element (XRE) regulator proteins play an important role in gene regulation in Streptomyces. In these bacteria, they are often encoded together with a small protein containing a DUF397 domain. Previous work on 15 such pairs present in S. coelicolor has shown they act as pleiotropic regulators. They dependently affect antibiotic production and morphological differentiation on different culture media. Overexpression of the protein Scr1, which is encoded by gene SCO4441, induces a drastic increase in the production of the antibiotic actinorhodin in this bacterium. This study involves a transcriptomic and metabolomic study of this overexpression.

Results: RNA-Seq assay showed that overexpression of Scr1 in the wild-type strain of S. coelicolor modified the expression of 1,308 genes at 36 h of culture incubation and 1339 at 48 h. The data indicated that almost 70% of the differentially expressed genes were up-regulated. Among them, 21% of the overexpressed genes were related to antibiotic biosynthesis pathways corresponding to antibiotics such as actinorhodin, calcium-dependent antibiotic (CDA), ectoin, arsono, hopene, coelimycin-P1, and albaflavenone. Conversely, some pathways were under-expressed such as those corresponding to coelichelin and undecylprodigiosin production. Metabolome studies corroborated these results and showed that the most notable differences in the production of these metabolites occurred at 72 and 96 h of incubation. A total of 3,978 and 4,392 metabolites were detected at 72 and 96 h respectively, from which 54 and 45 adducts corresponding to 15 and 14 secondary metabolites were identified. Of these, 5-hydroxyectoine, actinorhodin, albaflavenone, coelichelin, and coelimycin P1 are a few examples. In addition, other metabolic processes were affected such as those associated with energy metabolism, protein synthesis, response to stress, and the transport of molecules.

Conclusions: The overexpression of Scr1 in S. coelicolor causes changes in the regulation of secondary metabolite biosynthesis that may be related to the alteration of several other important primary metabolites. This transcriptional and metabolomic analysis takes a step forward in elucidating the pleiotropic role of the Scr1 protein in developmental processes and its importance in the biosynthesis of secondary metabolites in S. coelicolor. A model of its regulatory network is presented.