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Kinetics of genetic switching into the state of bacterial competence.

ABSTRACT: Nonlinear amplification of gene expression of master regulators is essential for cellular differentiation. Here we investigated determinants that control the kinetics of the genetic switching process from the vegetative state (B-state) to the competent state (K-state) of Bacillus subtilis, explicitly including the switching window which controls the probability for competence initiation in a cell population. For individual cells, we found that after initiation of switching, the levels of the master regulator [ComK](t) increased with sigmoid shape and saturation occurred at two distinct levels of [ComK]. We analyzed the switching kinetics into the state with highest [ComK] and found saturation after a switching period of length 1.4 +/- 0.3 h. The duration of the switching period was robust against variations in the gene regulatory network of the master regulator, whereas the saturation levels showed large variations between individual isogenic cells. We developed a nonlinear dynamics model, taking into account low-number stochastic effects. The model quantitatively describes the probability and timescale of switching at the single cell level and explains why the ComK level in the K-state is highly sensitive to extrinsic parameter variations. Furthermore, the model predicts a transition from stochastic to deterministic switching at increased production rates of ComK in agreement with experimental data.

SUBMITTER: Leisner M

PROVIDER: S-EPMC2716573 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Kinetics of genetic switching into the state of bacterial competence.

Leisner Madeleine M Kuhr Jan-Timm JT Rädler Joachim O JO Frey Erwin E Maier Berenike B

Biophysical journal 20090201 3

Nonlinear amplification of gene expression of master regulators is essential for cellular differentiation. Here we investigated determinants that control the kinetics of the genetic switching process from the vegetative state (B-state) to the competent state (K-state) of Bacillus subtilis, explicitly including the switching window which controls the probability for competence initiation in a cell population. For individual cells, we found that after initiation of switching, the levels of the mas ...[more]

PMID: 19186153

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Project description:Streptococcus pneumoniae (the pneumococcus) is a naturally competent organism that causes diseases such as pneumonia, otitis media, and bacteremia. The essential bacterial second messenger cyclic di-AMP (c-di-AMP) is an emerging player in the stress responses of many pathogens. In S. pneumoniae, c-di-AMP is produced by a diadenylate cyclase, CdaA, and cleaved by phosphodiesterases Pde1 and Pde2. c-di-AMP binds a transporter of K+ (Trk) family protein, CabP, which subsequently halts K+ uptake via the transporter TrkH. Recently, it was reported that Pde1 and Pde2 are essential for pneumococcal virulence in mouse models of disease. To elucidate c-di-AMP-mediated transcription that may lead to changes in pathogenesis, we compared the transcriptomes of wild-type (WT) and Δpde1 Δpde2 strains by transcriptome sequencing (RNA-Seq) analysis. Notably, we found that many competence-associated genes are significantly upregulated in the Δpde1 Δpde2 strain compared to the WT. These genes play a role in DNA uptake, recombination, and autolysis. Competence is induced by a quorum-sensing mechanism initiated by the secreted factor competence-stimulating peptide (CSP). Surprisingly, the Δpde1 Δpde2 strain exhibited reduced transformation efficiency compared to WT bacteria, which was c-di-AMP dependent. Transformation efficiency was also directly related to the [K+] in the medium, suggesting a link between c-di-AMP function and the pneumococcal competence state. We found that a strain that possesses a V76G variation in CdaA produced less c-di-AMP and was highly susceptible to CSP. Deletion of cabP and trkH restored the growth of these bacteria in medium with CSP. Overall, our study demonstrates a novel role for c-di-AMP in the competence program of S. pneumoniaeIMPORTANCE Genetic competence in bacteria leads to horizontal gene transfer, which can ultimately affect antibiotic resistance, adaptation to stress conditions, and virulence. While the mechanisms of pneumococcal competence signaling cascades have been well characterized, the molecular mechanism behind competence regulation is not fully understood. The bacterial second messenger c-di-AMP has previously been shown to play a role in bacterial physiology and pathogenesis. In this study, we provide compelling evidence for the interplay between c-di-AMP and the pneumococcal competence state. These findings not only attribute a new biological function to this dinucleotide as a regulator of competence, transformation, and survival under stress conditions in pneumococci but also provide new insights into how pneumococcal competence is modulated.

Dataset Information

Kinetics of genetic switching into the state of bacterial competence.

Publications

Kinetics of genetic switching into the state of bacterial competence.

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