High-Throughput GoMiner, an 'industrial-strength' integrative gene ontology tool for interpretation of multiple-microarray experiments, with application to studies of Common Variable Immune Deficiency (CVID)

Zeebèrg, Barry R.; Qin, Haiying; Narasimhan, Sudarshan; Sunshine, Margot; Cao, Hong; Kane, David W.; Reimers, Mark; Stephens, Robert M.; Bryant, David; Burt, Stanley K.; Elnekave, Eldad; Hari, Danielle M.; Wynn, Thomas A.; Cunningham‐Rundles, Charlotte; Stewart, Dawn; Nelson, David E.; Weinstein, John N.

doi:10.1186/1471-2105-6-168

Cited by 245 publications

(113 citation statements)

References 38 publications

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“…S5B in the supplemental material). Additionally, a gene ontology analysis using GoMiner (43) identified genes in the category of pathogenesis, including proteases (spl, ssp, and aur) and toxins, as the most highly enriched category of genes that are overexpressed in the ⌬sarA mutant, consistent with previous ⌬sarA mutant transcriptomics studies (60)(61)(62)(63). Interestingly, the ⌬sarA mutant is not the only NO˙-sensitive mutant we identified that overproduces proteases; the ⌬codY and ⌬rot mutants have also been characterized as overproducers of at least several of the 10 extracellular proteases secreted by S. aureus (64)(65)(66)(67)(68)(69).…”

Section: Resultsmentioning

confidence: 99%

Regulatory Requirements for Staphylococcus aureus Nitric Oxide Resistance

et al. 2016

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The ability of Staphylococcus aureus to resist host innate immunity augments the severity and pervasiveness of its pathogenesis. Nitric oxide (NO˙) is an innate immune radical that is critical for the efficient clearance of a wide range of microbial pathogens. Exposure of microbes to NO˙typically results in growth inhibition and induction of stress regulons. S. aureus, however, induces a metabolic state in response to NO˙that allows for continued replication and precludes stress regulon induction. The regulatory factors mediating this distinctive response remain largely undefined. Here, we employ a targeted transposon screen and transcriptomics to identify and characterize five regulons essential for NO˙resistance in S. aureus: three virulence regulons not formerly associated with NO˙resistance, SarA, CodY, and Rot, as well as two regulons with established roles, Fur and SrrAB. We provide new insights into the contributions of Fur and SrrAB during NO˙stress and show that the S. aureus ⌬sarA mutant, the most sensitive of the newly identified mutants, exhibits metabolic dysfunction and widespread transcriptional dysregulation following NO˙exposure. Altogether, our results broadly characterize the regulatory requirements for NO˙resistance in S. aureus and suggest an intriguing overlap between the regulation of NO˙resistance and virulence in this well-adapted human pathogen. IMPORTANCEThe prolific human pathogen Staphylococcus aureus is uniquely capable of resisting the antimicrobial radical nitric oxide (NO˙), a crucial component of the innate immune response. However, a complete understanding of how S. aureus regulates an effective response to NO˙is lacking. Here, we implicate three central virulence regulators, SarA, CodY, and Rot, as major players in the S. aureus NO˙response. Additionally, we elaborate on the contribution of two regulators, SrrAB and Fur, already known to play a crucial role in S. aureus NO˙resistance. Our study sheds light on a unique facet of S. aureus pathogenicity and demonstrates that the transcriptional response of S. aureus to NO˙is highly pleiotropic and intrinsically tied to metabolism and virulence regulation. The versatile Gram-positive pathogen Staphylococcus aureus is the leading cause of skin and soft tissue infections (SSTIs) in the United States but can also cause more severe illnesses, including pneumonia, osteomyelitis, endocarditis, and bacteremia (1-5). The ability of S. aureus to infect virtually every tissue of the body can be partially attributed to its extensive capacity for subverting host immunity. One unique defense of S. aureus against the immune system is resistance to nitric oxide (NO˙), a membrane-permeable radical and broad-spectrum innate immune effector required for the clearance of bacterial, viral, and fungal pathogens (6). The ability of S. aureus to continue growth in the presence of NO˙at concentrations that are inhibitory to other bacteria, including closely related staphylococci, contributes to its invasiveness and pathogenic success. For example...

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Section: Resultsmentioning

confidence: 99%

Regulatory Requirements for Staphylococcus aureus Nitric Oxide Resistance

et al. 2016

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“…To identify the biological pathways involved in human parturition, the set of proteins that changed during labour was mapped by GoMiner, using the whole genome as reference and limiting the analysis to the human database (Zeeberg et al 2005). A further pathway analysis was carried out through the use of IPA (Ingenuity Systems, www.ingenuity.…”

Section: In Silico Analysis Of Parturition Pathwaysmentioning

confidence: 99%

Low abundance plasma proteins in labour

Wang¹,

Heesom²,

Phillips³

et al. 2012

Reproduction

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Every year, millions of births worldwide are complicated by prematurity or difficult post-term deliveries, resulting in a high incidence of perinatal mortality and morbidity. Our poor understanding of human parturition is a key reason for our inability to improve the management of preterm and post-term birth. In this study, we used proteomic techniques to look into protein changes in placental blood plasma obtained from women before or after spontaneous or induced labour, with vaginal or caesarean section deliveries. Our aim was to understand the basic mechanisms of human parturition regardless of whether the signals that trigger labour are of maternal and/or fetal origin. We found proteins from 33 genes with significantly altered expression profiles in relation to mode of labour and delivery. Most changes in labour occurred in proteins associated with 'immune and defence responses'. Although the signal transduction and regulation of these pathways varied among modes of delivery, hepatocyte nuclear factor 1 homeobox A emerged as a shared protein in the mechanism of labour. Moreover, several apolipoproteins such as apolipoprotein A-IV and APOE were found to change with labour, and these changes were also confirmed in maternal plasma. This study has identified significant protein changes in placental intervillous plasma with labour and has revealed several pathways related to human parturition.

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“…In our case, the false discovery rate was set to a stringent level of 5 per cent. Differentially exposed genes (DEGs) showing a fold change of two were further analysed with regard to their molecular functions, biological processes and biological pathways using information provided by Wormbase (www.wormbase.org) with high throughput GOMINER software (Zeeberg et al 2005). CATEGORIZER software was used to summarize gene ontology terms (Hu et al 2008).…”

Section: Microarray Data Analysismentioning

confidence: 99%

Bio-electrospraying the nematode Caenorhabditis elegans : studying whole-genome transcriptional responses and key life cycle parameters

Mongkoldhumrongkul

Swain

Jayasinghe

et al. 2009

J. R. Soc. Interface.

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Bio-electrospray, the direct jet-based cell handling approach, is able to handle a wide range of cells (spanning immortalized, primary to stem cells). Studies at the genomic, genetic and the physiological levels have shown that, post-treatment, cellular integrity is unperturbed and a high percentage (more than 70%, compared with control) of cells remain viable. Although, these results are impressive, it may be argued that cell-based systems are oversimplistic. Therefore, it is important to evaluate the bio-electrospray technology using sensitive and dynamically developing multi-cellular organisms that share, at least some, similarities with multi-cell microenviorments encountered with tissues and organs. This study addressed this issue by using a well-characterized model organism, the non-parasitic nematode Caenorhabditis elegans. Nematode cultures were subjected to bio-electrospraying and compared with positive (heat shock) and negative controls (appropriate laboratory culture controls). Overall, bio-electrospraying did not modulate the reproductive output or induce significant changes in in vivo stress-responsive biomarkers (heat shock proteins). Likewise, whole-genome transcriptomics could not identify any biological processes, cellular components or molecular functions (gene ontology terms) that were significantly enriched in response to bio-electrospraying. This demonstrates that bio-electrosprays can be safely applied directly to nematodes and underlines its potential future use in the creation of multi-cellular environments within clinical applications.

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High-Throughput GoMiner, an 'industrial-strength' integrative gene ontology tool for interpretation of multiple-microarray experiments, with application to studies of Common Variable Immune Deficiency (CVID)

Cited by 245 publications

References 38 publications

Regulatory Requirements for Staphylococcus aureus Nitric Oxide Resistance

Regulatory Requirements for Staphylococcus aureus Nitric Oxide Resistance

Low abundance plasma proteins in labour

Bio-electrospraying the nematode Caenorhabditis elegans : studying whole-genome transcriptional responses and key life cycle parameters

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