Analysis of metabolomic PCA data using tree diagrams

Werth, Mark T.; Halouska, Steven M; Shortridge, Matthew D.; Zhang, Bo; Powers, Robert

doi:10.1016/j.ab.2009.12.022

Cited by 53 publications

(59 citation statements)

References 36 publications

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“…The OPLS-DA models were validated by using a modified leave-one-out method (34,35) and analysis of variance of cross-validated residuals (CV-ANOVA) (36). The metabolomics tree diagrams (dendrograms) and the ellipses corresponding to the 95% confidence limits from a normal distribution for each cluster within the PCA score plots were generated by using our PCA/PLS-DA utilities (http://bionmr.unl.edu/pca-utils.php) (37,38).…”

Section: Methodsmentioning

confidence: 99%

Influence of Iron and Aeration on Staphylococcus aureus Growth, Metabolism, and Transcription

et al. 2014

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Staphylococcus aureus is a prominent nosocomial pathogen and a major cause of biomaterial-associated infections. The success of S. aureus as a pathogen is due in part to its ability to adapt to stressful environments. As an example, the transition from residing in the nares to residing in the blood or deeper tissues is accompanied by changes in the availability of nutrients and elements such as oxygen and iron. As such, nutrients, oxygen, and iron are important determinants of virulence factor synthesis in S. aureus. In addition to influencing virulence factor synthesis, oxygen and iron are critical cofactors in enzymatic and electron transfer reactions; thus, a change in iron or oxygen availability alters the bacterial metabolome. Changes in metabolism create intracellular signals that alter the activity of metabolite-responsive regulators such as CodY, RpiRc, and CcpA. To assess the extent of metabolomic changes associated with oxygen and iron limitation, S. aureus cells were cultivated in iron-limited medium and/or with decreasing aeration, and the metabolomes were examined by nuclear magnetic resonance (NMR) spectroscopy. As expected, oxygen and iron limitation dramatically decreased tricarboxylic acid (TCA) cycle activity, creating a metabolic block and significantly altering the metabolome. These changes were most prominent during post-exponential-phase growth, when TCA cycle activity was maximal. Importantly, many of the effects of iron limitation were obscured by aeration limitation. Aeration limitation not only obscured the metabolic effects of iron limitation but also overrode the transcription of iron-regulated genes. Finally, in contrast to previous speculation, we confirmed that acidification of the culture medium occurs independent of the availability of iron.

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Section: Methodsmentioning

confidence: 99%

Influence of Iron and Aeration on Staphylococcus aureus Growth, Metabolism, and Transcription

et al. 2014

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“…Metabolomic Dendrogram-The relative clustering patterns in the PCA two-dimensional scores plots were quantitatively analyzed using a tree diagram and bootstrapping technique (40). The PC1 and PC2 scores for each set of 10 duplicate NMR spectra representing a specific metabolic state (iron limitation, ethanol treatment, etc.)…”

Section: Methodsmentioning

confidence: 99%

“…The common metabolomic response to environmental stimuli can be more easily observed by a recently developed method to visualize PCA data (40). By calculating an average position for each data set, such that each PC value (PC1, PC2, etc.)…”

Section: Table 1 Metabolites That Have Increased or Decreased Concentmentioning

confidence: 99%

Using NMR Metabolomics to Investigate Tricarboxylic Acid Cycle-dependent Signal Transduction in Staphylococcus epidermidis

Sadykov

Zhang

Halouska

et al. 2010

Journal of Biological Chemistry

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Staphylococcus epidermidis is a skin-resident bacterium and a major cause of biomaterial-associated infections. The transition from residing on the skin to residing on an implanted biomaterial is accompanied by regulatory changes that facilitate bacterial survival in the new environment. These regulatory changes are dependent upon the ability of bacteria to "sense" environmental changes. In S. epidermidis, disparate environmental signals can affect synthesis of the biofilm matrix polysaccharide intercellular adhesin (PIA). Previously, we demonstrated that PIA biosynthesis is regulated by tricarboxylic acid (TCA) cycle activity. The observations that very different environmental signals result in a common phenotype (i.e. increased PIA synthesis) and that TCA cycle activity regulates PIA biosynthesis led us to hypothesize that S. epidermidis is "sensing" disparate environmental signals through the modulation of TCA cycle activity. In this study, we used NMR metabolomics to demonstrate that divergent environmental signals are transduced into common metabolomic changes that are "sensed" by metabolite-responsive regulators, such as CcpA, to affect PIA biosynthesis. These data clarify one mechanism by which very different environmental signals cause common phenotypic changes. In addition, due to the frequency of the TCA cycle in diverse genera of bacteria and the intrinsic properties of TCA cycle enzymes, it is likely the TCA cycle acts as a signal transduction pathway in many bacteria.Staphylococcus epidermidis is a skin-resident, opportunistic pathogen that is the leading cause of hospital-associated infections (1). Although the type and severity of diseases produced by this bacterium varies, its most common infectious manifestation is associated with implanted biomaterials. The dramatic environmental changes that occur during the transition from being skin-resident to residing on implanted biomaterials necessitates the need for changes in the expression of genes coding for enzymes required for growth in the new environment. This environmental adaptation often includes activating transcription of virulence genes; hence, most virulence genes are regulated by environmental and nutritional signals (2). Accordingly, a major area of interest in microbiology is determining how bacteria "sense" and respond to environmental signals. Given the tremendous diversity of microbial life, it is not surprising that the mechanisms bacteria employ are equally diverse. These mechanisms include two-component regulatory systems, alternative factors, mechanosensors, small RNAs, riboswitches, and many others. Although remarkable advances have been made in identifying the response regulators, our knowledge of signaling mechanisms has lagged behind, the exception being cell-density signaling.The tricarboxylic acid (TCA) cycle has been implicated as regulating or affecting staphylococcal virulence and/or virulence determinant biosynthesis (3-9). The TCA cycle has three primary functions: (i) to provide biosynthetic intermediates, (ii) to gen...

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“…Our PCA/projection to latent structures discriminate analysis utilities were used for statistical analysis of group separation in the PCA and orthogonal projection to latent structures discriminate analysis scores plots (38,39). Statistical significances for other results were assessed using Student's t test or MannWhitney U test.…”

Section: Determination Of Transcriptional Start Sites Of Nmmn_0640mentioning

confidence: 99%

Catabolite Control Protein E (CcpE) Is a LysR-type Transcriptional Regulator of Tricarboxylic Acid Cycle Activity in Staphylococcus aureus

Hartmann

Zhang

Baronian

et al. 2013

Journal of Biological Chemistry

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Background:The TCA cycle is a central metabolic pathway that facilitates the adaption of bacteria to a nutrient-limited environment. Results: Inactivation of CcpE in Staphylococcus aureus resulted in a decreased transcription of the aconitase encoding gene citB, and reduced TCA cycle activity. Conclusion: CcpE affects the TCA cycle via direct transcriptional control of citB. Significance: This is the first positive regulator of TCA cycle activity identified in this pathogen.

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Analysis of metabolomic PCA data using tree diagrams

Cited by 53 publications

References 36 publications

Influence of Iron and Aeration on Staphylococcus aureus Growth, Metabolism, and Transcription

Influence of Iron and Aeration on Staphylococcus aureus Growth, Metabolism, and Transcription

Using NMR Metabolomics to Investigate Tricarboxylic Acid Cycle-dependent Signal Transduction in Staphylococcus epidermidis

Catabolite Control Protein E (CcpE) Is a LysR-type Transcriptional Regulator of Tricarboxylic Acid Cycle Activity in Staphylococcus aureus

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