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Analysis of genes that encode DtxR-like transcriptional regulators in pathogenic and saprophytic corynebacterial species.

ABSTRACT: Metal-dependent transcriptional regulators of the diphtheria toxin repressor (DtxR) family have been identified in a wide variety of bacterial genera, where they control gene expression in response to one of two metal ions, Fe(2+) or Mn(2+). DtxR of Corynebacterium diphtheriae is the best characterized of these important metal-dependent regulators. The genus Corynebacterium includes many phenotypically diverse species, and the prevalence of DtxR-like regulators within the genus is unknown. We assayed chromosomal DNA from 42 different corynebacterial isolates, representing 33 different species, for the presence of a highly conserved region of the dtxR gene that encodes the DNA-binding helix-turn-helix motif and metal-binding site 1 within domains 1 and 2 of DtxR. The chromosome of all of the isolates contained this conserved region of dtxR, and DNA sequencing revealed a high level of nucleotide sequence conservation within this region in all of the corynebacterial species (ranging from 62 to 100% identity and averaging 70% identity with the dtxR prototype). The level of identity was even greater for the predicted protein sequences encoded by the dtxR-like genes, ranging from 81 to 100% identity and averaging 91% identity with DtxR. Using a DtxR-specific antiserum we confirmed the presence of a DtxR-like protein in extracts of most of the corynebacterial isolates and determined the precise amount of DtxR per cell in C. diphtheriae. The high level of identity at both DNA and protein levels suggests that all of the isolates tested encode a functional DtxR-like Fe(2+)-activated regulatory protein that can bind homologs of the DtxR operator and regulate gene expression in response to iron.

SUBMITTER: Oram DM

PROVIDER: S-EPMC375144 | biostudies-literature | 2004 Apr

REPOSITORIES: biostudies-literature

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Analysis of genes that encode DtxR-like transcriptional regulators in pathogenic and saprophytic corynebacterial species.

Oram Diana Marra DM Avdalovic Ana A Holmes Randall K RK

Infection and immunity 20040401 4

Metal-dependent transcriptional regulators of the diphtheria toxin repressor (DtxR) family have been identified in a wide variety of bacterial genera, where they control gene expression in response to one of two metal ions, Fe(2+) or Mn(2+). DtxR of Corynebacterium diphtheriae is the best characterized of these important metal-dependent regulators. The genus Corynebacterium includes many phenotypically diverse species, and the prevalence of DtxR-like regulators within the genus is unknown. We as ...[more]

PMID: 15039307

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Project description:BackgroundThe genus Sporothrix belongs to the order Ophiostomatales and contains mainly saprobic soil and plant fungi, although pathogenic species capable of causing human infections are also present. The whole-genomes of disease-causing species have already been sequenced and annotated but no comprehensive genomic resources for environmental Sporothrix species are available, thus limiting our understanding of the evolutionary origin of virulence-related genes and pathogenicity.ResultThe genome assembly of four environmental Sporothrix species resulted in genome size of ~ 30.9 Mbp in Sporothrix phasma, ~ 35 Mbp in S. curviconia, ~ 38.7 Mbp in S. protearum, and ~ 39 Mbp in S. variecibatus, with a variable gene content, ranging from 8142 (S. phasma) to 9502 (S. variecibatus). The analysis of mobile genetic elements showed significant differences in the content of transposable elements within the sequenced genomes, with the genome of S. phasma lacking several class I and class II transposons, compared to the other Sporothrix genomes investigated. Moreover, the comparative analysis of orthologous genes shared by clinical and environmental Sporothrix genomes revealed the presence of 3622 orthogroups shared by all species, whereas over 4200 genes were species-specific single-copy gene products. Carbohydrate-active enzyme analysis revealed a total of 2608 protein-coding genes containing single and/or multiple CAZy domains, resulting in no statistically significant differences among pathogenic and environmental species. Nevertheless, some families were not found in clinical species. Furthermore, for each sequenced Sporothrix species, the mitochondrial genomes was assembled in a single circular DNA molecule, ranging from 25,765 bp (S. variecibatus) to 58,395 bp (S. phasma).ConclusionIn this study, we present four annotated genome assemblies generated using PacBio SMRT sequencing data from four environmental species: S. curviconia, S. phasma, S. protearum and S. variecibatus with the aim to provide a starting point for future comparative genome evolution studies addressing species diversification, ecological/host adaptation and origin of pathogenic lineages within the genus Sporothrix.

Project description:The human commensal and opportunistic fungal pathogen Candida albicans displays extensive genetic and phenotypic variation across clinical isolates. Here, we performed RNA sequencing on 21 well-characterized isolates to examine how genetic variation contributes to gene expression differences and to link these differences to phenotypic traits. C. albicans adapts primarily through clonal evolution, and yet hierarchical clustering of gene expression profiles in this set of isolates did not reproduce their phylogenetic relationship. Strikingly, strain-specific gene expression was prevalent in some strain backgrounds. Association of gene expression with phenotypic data by differential analysis, linear correlation, and assembly of gene networks connected both previously characterized and novel genes with 23 C. albicans traits. Construction of de novo gene modules produced a gene atlas incorporating 67% of C. albicans genes and revealed correlations between expression modules and important phenotypes such as systemic virulence. Furthermore, targeted investigation of two modules that have novel roles in growth and filamentation supported our bioinformatic predictions. Together, these studies reveal widespread transcriptional variation across C. albicans isolates and identify genetic and epigenetic links to phenotypic variation based on coexpression network analysis.IMPORTANCE Infectious fungal species are often treated uniformly despite clear evidence of genotypic and phenotypic heterogeneity being widespread across strains. Identifying the genetic basis for this phenotypic diversity is extremely challenging because of the tens or hundreds of thousands of variants that may distinguish two strains. Here, we use transcriptional profiling to determine differences in gene expression that can be linked to phenotypic variation among a set of 21 Candida albicans isolates. Analysis of this transcriptional data set uncovered clear trends in gene expression characteristics for this species and new genes and pathways that were associated with variation in pathogenic processes. Direct investigation confirmed functional predictions for a number of new regulators associated with growth and filamentation, demonstrating the utility of these approaches in linking genes to important phenotypes.

Project description:Network analysis is a novel method to understand the complex pathogenesis of inflammation-driven atherosclerosis. Using this approach, we attempted to identify key inflammatory genes and their core transcriptional regulators in coronary artery disease (CAD). Initially, we obtained 124 candidate genes associated with inflammation and CAD using Polysearch and CADgene database for which protein-protein interaction network was generated using STRING 9.0 (Search Tool for the Retrieval of Interacting Genes) and visualized using Cytoscape v 2.8.3. Based on betweenness centrality (BC) and node degree as key topological parameters, we identified interleukin-6 (IL-6), vascular endothelial growth factor A (VEGFA), interleukin-1 beta (IL-1B), tumor necrosis factor (TNF) and prostaglandin-endoperoxide synthase 2 (PTGS2) as hub nodes. The backbone network constructed with these five hub genes showed 111 nodes connected via 348 edges, with IL-6 having the largest degree and highest BC. Nuclear factor kappa B1 (NFKB1), signal transducer and activator of transcription 3 (STAT3) and JUN were identified as the three core transcription factors from the regulatory network derived using MatInspector. For the purpose of validation of the hub genes, 97 test networks were constructed, which revealed the accuracy of the backbone network to be 0.7763 while the frequency of the hub nodes remained largely unaltered. Pathway enrichment analysis with ClueGO, KEGG and REACTOME showed significant enrichment of six validated CAD pathways - smooth muscle cell proliferation, acute-phase response, calcidiol 1-monooxygenase activity, toll-like receptor signaling, NOD-like receptor signaling and adipocytokine signaling pathways. Experimental verification of the above findings in 64 cases and 64 controls showed increased expression of the five candidate genes and the three transcription factors in the cases relative to the controls (p<0.05). Thus, analysis of complex networks aid in the prioritization of genes and their transcriptional regulators in complex diseases.

Dataset Information

Analysis of genes that encode DtxR-like transcriptional regulators in pathogenic and saprophytic corynebacterial species.

Publications

Analysis of genes that encode DtxR-like transcriptional regulators in pathogenic and saprophytic corynebacterial species.

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