Dataset Information

Global Effects of the Developmental Regulator BldB in Streptomyces venezuelae.

ABSTRACT: In Streptomyces, the Bld (Bald) regulators control formation of the reproductive aerial hyphae. The functions of some of these regulators have been well characterized, but BldB has remained enigmatic. In addition to the bldB gene itself, Streptomyces venezuelae has 10 paralogs of bldB that sit next to paralogs of whiJ and abaA. Transcriptome sequencing (RNA-seq) revealed that loss of BldB function causes the dramatic transcriptional upregulation of the abaA paralogs and a novel inhibitor of sporulation, iosA, and that cooverexpression of just two of these genes, iosA and abaA6, was sufficient to recapitulate the bldB mutant phenotype. Further RNA-seq analysis showed that the transcription factor WhiJ9 is required for the activation of iosA seen in the bldB mutant, and biochemical studies showed that WhiJ9 mediates the activation of iosA expression by binding to direct repeats in the iosA-whiJ9 intergenic region. BldB and BldB9 hetero-oligomerize, providing a potential link between BldB and the iosA-whiJ9-bldB9 locus. This work greatly expands our overall understanding of the global effects of the BldB developmental regulator. IMPORTANCE To reproduce and disperse, the filamentous bacterium Streptomyces develops specialized reproductive structures called aerial hyphae. The formation of these structures is controlled by the bld (bald) genes, many of which encode transcription factors whose functions have been characterized. An exception is BldB, a protein whose biochemical function is unknown. In this study, we gain insight into the global effects of BldB function by examining the genome-wide transcriptional effects of deleting bldB. We identify a small set of genes that are dramatically upregulated in the absence of BldB. We show that their overexpression causes the bldB phenotype and characterize a transcription factor that mediates the upregulation of one of these target genes. Our results provide new insight into how BldB influences Streptomyces development.

SUBMITTER: Avramova MM

PROVIDER: S-EPMC10294661 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Global Effects of the Developmental Regulator BldB in Streptomyces venezuelae.

Avramova Marieta M MM Stevenson Clare E M CEM Chandra Govind G Holmes Neil A NA Bush Matthew J MJ Findlay Kim C KC Buttner Mark J MJ

Journal of bacteriology 20230530 6

In Streptomyces, the Bld (Bald) regulators control formation of the reproductive aerial hyphae. The functions of some of these regulators have been well characterized, but BldB has remained enigmatic. In addition to the bldB gene itself, Streptomyces venezuelae has 10 paralogs of bldB that sit next to paralogs of whiJ and abaA. Transcriptome sequencing (RNA-seq) revealed that loss of BldB function causes the dramatic transcriptional upregulation of the abaA< ...[more]

PMID: 37249447

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Project description:Cyclic AMP receptor protein (Crp) is a transcription regulator controlling diverse cellular processes in many bacteria. In Streptomyces coelicolor, it is well established that Crp plays a critical role in spore germination and colony development. Here, we demonstrate that Crp is a key regulator of secondary metabolism and antibiotic production in S. coelicolor and show that it may additionally coordinate precursor flux from primary to secondary metabolism. We found that crp deletion adversely affected the synthesis of three well-characterized antibiotics in S. coelicolor: actinorhodin (Act), undecylprodigiosin (Red), and calcium-dependent antibiotic (CDA). Using chromatin immunoprecipitation-microarray (ChIP-chip) assays, we determined that eight (out of 22) secondary metabolic clusters encoded by S. coelicolor contained Crp-associated sites. We followed the effect of Crp induction using transcription profiling analyses and found secondary metabolic genes to be significantly affected: included in this Crp-dependent group were genes from six of the clusters identified in the ChIP-chip experiments. Overexpressing Crp in a panel of Streptomyces species led to enhanced antibiotic synthesis and new metabolite production, suggesting that Crp control over secondary metabolism is broadly conserved in the streptomycetes and that Crp overexpression could serve as a powerful tool for unlocking the chemical potential of these organisms. IMPORTANCE Streptomyces produces a remarkably diverse array of secondary metabolites, including many antibiotics. In recent years, genome sequencing has revealed that these products represent only a small proportion of the total secondary metabolite potential of Streptomyces. There is, therefore, considerable interest in discovering ways to stimulate the production of new metabolites. Here, we show that Crp (the classical regulator of carbon catabolite repression in Escherichia coli) is a master regulator of secondary metabolism in Streptomyces. It binds to eight of 22 secondary metabolic gene clusters in the Streptomyces coelicolor genome and directly affects the expression of six of these. Deletion of crp in S. coelicolor leads to dramatic reductions in antibiotic levels, while Crp overexpression enhances antibiotic production. We find that the antibiotic-stimulatory capacity of Crp extends to other streptomycetes, where its overexpression activates the production of "cryptic" metabolites that are not otherwise seen in the corresponding wild-type strain.

Project description:In members of genus Streptomyces, AdpA is a master transcriptional regulator that controls the expression of hundreds of genes involved in morphological differentiation, secondary metabolite biosynthesis, chromosome replication, etc. However, the function of AdpASv, an AdpA ortholog of Streptomyces venezuelae, is unknown. This bacterial species is a natural producer of chloramphenicol and has recently become a model organism for studies on Streptomyces. Here, we demonstrate that AdpASv is essential for differentiation and antibiotic biosynthesis in S. venezuelae and provide evidence suggesting that AdpASv positively regulates its own gene expression. We speculate that the different modes of AdpA-dependent transcriptional autoregulation observed in S. venezuelae and other Streptomyces species reflect the arrangement of AdpA binding sites in relation to the transcription start site. Lastly, we present preliminary data suggesting that AdpA may undergo a proteolytic processing and we speculate that this may potentially constitute a novel regulatory mechanism controlling cellular abundance of AdpA in Streptomyces. IMPORTANCEStreptomyces are well-known producers of valuable secondary metabolites which include a large variety of antibiotics and important model organisms for developmental studies in multicellular bacteria. The conserved transcriptional regulator AdpA of Streptomyces exerts a pleiotropic effect on cellular processes, including the morphological differentiation and biosynthesis of secondary metabolites. Despite extensive studies, the function of AdpA in these processes remains elusive. This work provides insights into the role of a yet unstudied AdpA ortholog of Streptomyces venezuelae, now considered a novel model organism. We found that AdpA plays essential role in morphological differentiation and biosynthesis of chloramphenicol, a broad-spectrum antibiotic. We also propose that AdpA may undergo a proteolytic processing that presumably constitutes a novel mechanism regulating cellular abundance of this master regulator.

Dataset Information

Global Effects of the Developmental Regulator BldB in Streptomyces venezuelae.

Publications

Global Effects of the Developmental Regulator BldB in Streptomyces venezuelae.

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