Abstract
Genome sequencing has revealed that actinomycetes possess the potential to produce many more secondary metabolites than previously thought. The existing challenge is to devise efficient methods to activate these silent biosynthetic gene clusters (BGCs). In Streptomyces ansochromogenes, disruption of wblA, a pleiotropic regulatory gene, activated the expression of cryptic tylosin analogues and abolished nikkomycin production simultaneously. Overexpressing pathway-specific regulatory genes tylR1 and tylR2 can also trigger the biosynthesis of silent tylosin analogues, in which TylR1 exerted its function via enhancing tylR2 expression. Bacterial one-hybrid system experiments unveiled that WblA directly inhibits the transcription of tylR1 and tylR2 to result in the silence of tylosin analogues BGC. Furthermore, WblA can activate the nikkomycin production through up-regulating the transcription of pleiotropic regulatory gene adpA. More interestingly, AdpA can activate sanG (an activator gene in nikkomycin BGC) but repress wblA. Our studies provide a valuable insight into the complex functions of pleiotropic regulators.
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Data availability
Genome sequence and RNAseq data presented in this study are openly available in China National Microbiology Data Center (NMDC), and the accession number of the BioProject is [NMDC10017856]. Data of genomic DNA of S. ansochromogenes 7100 can be found under accession number NMDC60029072. RNA-seq data of S. ansochromogenes 7100 can be found under accession number NMDC40009909 (WT_24h), NMDC40009910 (WT_48h), NMDC40009911 (ΔwblA_24h), and NMDC40009912 (ΔwblA_48h).
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Acknowledgements
This work was supported by the National Key Research and Development Program of China (2020YFA0907800), the National Natural Science Foundation of China (32170043, 82173720) and the Beijing Natural Science Foundation (7212153). We thank Dr. Cheng Lu for his assistance in EMSA experiments of AdpA to its targets P wblA, construction of ΔwblA-pks1 and partial HPLC analysis. We would like to thank Professor Zhengguo He (College of Life Science and Technology, Guangxi University, Nanning, China) for kindly providing bacterial one-hybrid reporter system pRomoter, pTRGMCM and reporter strain E. coli XL1-Blue MRF’ Kan strain.
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Li, Y., Guan, H., Li, J. et al. An intricate regulation of WblA controlling production of silent tylosin analogues and abolishment of expressible nikkomycin. Sci. China Life Sci. 66, 612–625 (2023). https://doi.org/10.1007/s11427-022-2199-1
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DOI: https://doi.org/10.1007/s11427-022-2199-1