Silencing cryptic specialized metabolism in Streptomyces by the nucleoid-associated protein Lsr2.

Emma J Gehrke,Sheila M Pimentel-Elardo,Xiafei Zhang,Justin R Nodwell,Christiaan A Rees,Stephanie E Jones,Andrew R Johnson,Jane E Hill,Sonya Turvey,Sebastian S Gehrke,Hindra Hindra,Erin E Carlson,Marie A Elliot,Suzanne Boursalie

doi:10.7554/elife.47691

Abstract

Lsr2 is a nucleoid-associated protein conserved throughout the actinobacteria, including the antibiotic-producing Streptomyces. Streptomyces species encode paralogous Lsr2 proteins (Lsr2 and Lsr2-like, or LsrL), and we show here that of the two, Lsr2 has greater functional significance. We found that Lsr2 binds AT-rich sequences throughout the chromosome, and broadly represses gene expression. Strikingly, specialized metabolic clusters were over-represented amongst its targets, and the cryptic nature of many of these clusters appears to stem from Lsr2-mediated repression. Manipulating Lsr2 activity in model species and uncharacterized isolates resulted in the production of new metabolites not seen in wild type strains. Our results suggest that the transcriptional silencing of biosynthetic clusters by Lsr2 may protect Streptomyces from the inappropriate expression of specialized metabolites, and provide global control over Streptomyces' arsenal of signaling and antagonistic compounds.

Highlights

Chromosome evolution in bacteria can be driven by mutation, genome rearrangement, and horizontal gene transfer, and work over the last decade has revealed that many bacteria have co-opted nucleoidassociated proteins to serve as ‘genome sentinels’, suppressing the inappropriate expression of newly acquired DNA (Dorman, 2007; Dorman, 2014)
The nucleoid-associated protein Lsr2 has been tied to virulence and environmental adaptation in Mycobacterium, and like H-NS in E. coli, it has been proposed to function to repress the expression of ‘foreign’ DNA (Gordon et al, 2010; Gordon et al, 2011)
Unlike more conventional transcription factors, we found that Lsr2 binding sites in S. venezuelae tended to be quite broad, centring on AT-rich sequences, extending hundreds of base-pairs, and frequently encompassing promoter regions (Supplementary file 3)

Summary

Introduction

Chromosome evolution in bacteria can be driven by mutation, genome rearrangement, and horizontal gene transfer, and work over the last decade has revealed that many bacteria have co-opted nucleoidassociated proteins to serve as ‘genome sentinels’, suppressing the inappropriate expression of newly acquired DNA (Dorman, 2007; Dorman, 2014). This is thought to maximize competitive fitness by repressing the expression of foreign DNA until it is either incorporated into the existing regulatory networks of the host, or decays to a point that it is lost from the chromosome (Navarre et al, 2007).

Methods

Results

Conclusion