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Construction and verification of the transcriptional regulatory response network of Streptococcus mutans upon treatment with the biofilm inhibitor carolacton
Citation Link: https://doi.org/10.15480/882.3526
Publikationstyp
Journal Article
Date Issued
2014-08-29
Sprache
English
Institut
TORE-DOI
TORE-URI
Journal
Volume
15
Issue
1
Article Number
362
Citation
BMC Genomics 15 (1): 362 (2014)
Publisher DOI
Scopus ID
PubMed ID
24884510
Publisher
BioMed Central
Background: Carolacton is a newly identified secondary metabolite causing altered cell morphology and death of Streptococcus mutans biofilm cells. To unravel key regulators mediating these effects, the transcriptional regulatory response network of S. mutans biofilms upon carolacton treatment was constructed and analyzed. A systems biological approach integrating time-resolved transcriptomic data, reverse engineering, transcription factor binding sites, and experimental validation was carried out.Results: The co-expression response network constructed from transcriptomic data using the reverse engineering algorithm called the Trend Correlation method consisted of 8284 gene pairs. The regulatory response network inferred by superimposing transcription factor binding site information into the co-expression network comprised 329 putative transcriptional regulatory interactions and could be classified into 27 sub-networks each co-regulated by a transcription factor. These sub-networks were significantly enriched with genes sharing common functions. The regulatory response network displayed global hierarchy and network motifs as observed in model organisms. The sub-networks modulated by the pyrimidine biosynthesis regulator PyrR, the glutamine synthetase repressor GlnR, the cysteine metabolism regulator CysR, global regulators CcpA and CodY and the two component system response regulators VicR and MbrC among others could putatively be related to the physiological effect of carolacton. The predicted interactions from the regulatory network between MbrC, known to be involved in cell envelope stress response, and the murMN-SMU_718c genes encoding peptidoglycan biosynthetic enzymes were experimentally confirmed using Electro Mobility Shift Assays. Furthermore, gene deletion mutants of five predicted key regulators from the response networks were constructed and their sensitivities towards carolacton were investigated. Deletion of cysR, the node having the highest connectivity among the regulators chosen from the regulatory network, resulted in a mutant which was insensitive to carolacton thus demonstrating not only the essentiality of cysR for the response of S. mutans biofilms to carolacton but also the relevance of the predicted network.Conclusion: The network approach used in this study revealed important regulators and interactions as part of the response mechanisms of S. mutans biofilm cells to carolacton. It also opens a door for further studies into novel drug targets against streptococci. © 2014 Sudhakar et al.; licensee BioMed Central Ltd.
Subjects
Biofilm inhibitor
Caries
Carolacton
Key regulators
Network verification
Reverse engineering
Streptococcus mutans
Transcriptional regulatory network
Transcriptome
DDC Class
570: Biowissenschaften, Biologie
Funding Organisations
More Funding Information
This study was done within the project “Development of biofilm inhibitors using a systems biology approach” (0315411) which is financed by the German Federal Ministry of Education and Research (BMBF) in the frame of the Research Program “Medical systems biology - MedSys”.
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1471-2164-15-739 Erratum.pdf
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