A functional genomics catalogue of activated transcription factors during pathogenesis of pneumococcal disease

Abstract

BackgroundStreptococcus pneumoniae (the pneumococcus) is the world’s foremost microbial pathogen, killing more people each year than HIV, TB or malaria. The capacity to penetrate deeper host tissues contributes substantially to the ability of this organism to cause disease. Here we investigated, for the first time, functional genomics modulation of 3 pneumococcal strains (serotype 2 [D39], serotype 4 [WCH43] and serotype 6A [WCH16]) during transition from the nasopharynx to lungs to blood and to brain of mice at both promoter and domain activation levels.ResultsWe found 7 highly activated transcription factors (TFs) [argR, codY, hup, rpoD, rr02, scrR and smrC] capable of binding to a large number of up-regulated genes, potentially constituting the regulatory backbone of pneumococcal pathogenesis. Strain D39 showed a distinct profile in employing a large number of TFs during blood infection. Interestingly, the same highly activated TFs used by D39 in blood are also used by WCH16 and WCH43 during brain infection. This indicates that different pneumococcal strains might activate a similar set of TFs and regulatory elements depending on the final site of infection. Hierarchical clustering analysis showed that all the highly activated TFs, except rpoD, clustered together with a high level of similarity in all 3 strains, which might suggest redundancy in the regulatory roles of these TFs during infection. Discriminant function analysis of the TFs in various niches highlights differential regulatory backgrounds of the 3 strains, and pathogenesis data confirms codY as the most significant predictor discriminating between these strains in various niches, particularly in the blood. Moreover, the predicted TF and domain activation profiles of the 3 strains correspond with their distinct pathogenicity characteristics.ConclusionsOur findings suggest that the pneumococcus changes the short binding sites in the promoter regions of genes in a niche-specific manner to enhance its ability to disseminate from one host niche to another. This study provides a framework for an improved understanding of the dynamics of pneumococcal pathogenesis, and opens a new avenue into similar investigations in other pathogenic bacteria.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-769) contains supplementary material, which is available to authorized users.

ManLMN is a glucose transporter and central metabolic regulator in Streptococcus pneumoniae

“…Mutations in smrC, encoding the LysR-family transcriptional regulator, SmrC, were the second most common type of mutation (Table 1). SmrC is considered to be a critical virulence regulator that is highly active during infections in mice (Lau et al, 2001;Mahdi et al, 2013Mahdi et al, , 2014. Mutations in smrC arose from selection on multiple carbohydrates suggesting SmrC has a global regulatory influence on carbohydrate metabolism.…”

Non‐coding and coding genomic variants distinguish prostate cancer, castration‐resistant prostate cancer, familial prostate cancer, and metastatic castration‐resistant prostate cancer from each other

“…In an interesting study, it was found that the 5′ UTR controls variant activity of ERG and of Tmprss2:ERG. Specific arrangements of regulatory elements and variants in upstream non‐coding regions of genes dictate diverse patterns of gene expression . Also, co‐expressed genes commonly share similar regulatory elements in their UTRs and promoter regions that bind specific transcription factors .…”

“…5,6 In fact, most biomarker/signature discovery studies have focused on coding regions and proteins, and the role of non-coding variants, including those seen in 3′ upstream untranslated regions (3′ UTR), 5′ UTR, intronic variants, and intergenic variants are largely neglected. 7 Non-coding variants may influence microRNA-mRNA interaction, epigenomic regulation, and alternative splicing in cancer induction and progression. The functional impact of intergenic variants in different diseases through alteration in chromatin structure of nearby genes has been documented.…”

A novel pairwise comparison method for in silico discovery of statistically significant cis-regulatory elements in eukaryotic promoter regions: Application to Arabidopsis

“…Some of the significant CREs may be associated with the differential expression of the two groups of genes in response to light. DOF proteins are plant specific transcription factors involved in seed development as well as signaling and response to light and phytohormone (Mahdi et al, 2014).…”

“…Recently, it has been demonstrated that CREs on the promoter regions of genes in wild wheat are more variable and frequent than the cultivated wheat which contributes in fast response and better understanding of environmental conditions for wild genotype (Babgohari et al, 2014). Due to the unique characteristic of transcription factors in binding to CREs on promoter regions of different genes, a small number of transcription factors are enough to regulate a considerable number of genes and play the central role in functional genomics (Mahdi et al, 2013;Mahdi et al, 2014). Interestingly, a small number of transcription factors and microRNAs, as the two main commanders of system biology, can regulate a genomic region involved in a particular phenomenon (hot spots) (Alisoltani et al, 2014).…”