Genomic reconstruction of transcriptional regulatory networks in lactic acid bacteria

BMC Genomics (Impact Factor: 3.99). 02/2013; 14(1):94. DOI: 10.1186/1471-2164-14-94
Source: PubMed


Genome scale annotation of regulatory interactions and reconstruction of regulatory networks are the crucial problems in bacterial genomics. The Lactobacillales order of bacteria collates various microorganisms having a large economic impact, including both human and animal pathogens and strains used in the food industry. Nonetheless, no systematic genome-wide analysis of transcriptional regulation has been previously made for this taxonomic group.

A comparative genomics approach was used for reconstruction of transcriptional regulatory networks in 30 selected genomes of lactic acid bacteria. The inferred networks comprise regulons for 102 orthologous transcription factors (TFs), including 47 novel regulons for previously uncharacterized TFs. Numerous differences between regulatory networks of the Streptococcaceae and Lactobacillaceae groups were described on several levels. The two groups are characterized by substantially different sets of TFs encoded in their genomes. Content of the inferred regulons and structure of their cognate TF binding motifs differ for many orthologous TFs between the two groups. Multiple cases of non-orthologous displacements of TFs that control specific metabolic pathways were reported.

The reconstructed regulatory networks substantially expand the existing knowledge of transcriptional regulation in lactic acid bacteria. In each of 30 studied genomes the obtained regulatory network contains on average 36 TFs and 250 target genes that are mostly involved in carbohydrate metabolism, stress response, metal homeostasis and amino acids biosynthesis. The inferred networks can be used for genetic experiments, functional annotations of genes, metabolic reconstruction and evolutionary analysis. All reconstructed regulons are captured within the Streptococcaceae and Lactobacillaceae collections in the RegPrecise database (

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Available from: Marat D Kazanov, Jan 22, 2015
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    • "The LacI family contains a number of global regulators for central carbohydrate metabolic pathways, in particular the previously known regulators CcpA in Firmicutes and FruR in Enterobacteria. Here, we report a comparative genomics reconstruction of orthologous FruR regulons in γ-Proteobacteria, while the reconstructions of CcpA regulons in different lineages of Firmicutes has been reported previously (Ravcheev et al., 2011, 2013b; Antunes et al., 2012; Leyn et al., 2013) and is available in "
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    ABSTRACT: DNA-binding transcription factors (TFs) are essential components of transcriptional regulatory networks in Bacteria. LacI-family TFs (LacI-TFs) are broadly distributed among certain lineages of bacteria. The majority of characterized LacI-TFs sense sugar effectors and regulate carbohydrate utilization genes. The comparative genomics approaches enable in silico identification of TF-binding sites and regulon reconstruction. To study function and evolution of LacI-TFs, we performed genomics-based reconstruction and comparative analysis of their regulons. For over 1,300 LacI-TFs from over 270 bacterial genomes, we predicted their cognate DNA-binding motifs and identified target genes. Using the genome context and metabolic subsystem analyses of reconstructed regulons we tentatively assigned functional roles and predicted candidate effectors for 78% and 67% of the analyzed LacI-TFs, respectively. Nearly 90% of the studied LacI-TFs are local regulators of sugar utilization pathways, whereas the remaining 125 global regulators control large and diverse sets of metabolic genes. The global LacI-TFs include the previously known regulators CcpA in Firmicutes, FruR in Enterobacteria, and PurR in Gammaproteobacteria, and the three novel regulators, GluR, GapR, and PckR, that are predicted to control the central carbohydrate metabolism in three lineages of Alphaproteobacteria. Phylogenetic analysis of regulators combined with the reconstructed regulons provides a model of evolutionary diversification of LacI-TFs. The obtained genomic collection of in silico reconstructed regulons in Bacteria is available in the RegPrecise database ( It provides a framework for future structural and functional classification of the LacI protein family and identification of molecular determinants of the DNA and ligand specificity. The inferred regulons can be also used for functional gene annotation and reconstruction of sugar catabolic networks in diverse bacteria.
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    • "Mechanisms of transcriptional regulation of L-Rha utilization genes are also poorly understood in many species beyond the models. With the availability of hundreds of sequenced bacterial genomes, it is possible to use comparative genomics to reconstruct metabolic pathways and regulatory networks in individual taxonomic groups of Bacteria (Rodionov et al., 2010, 2011; Ravcheev et al., 2011, 2013; Leyn et al., 2013). Genome contextbased techniques, including the analysis of chromosomal gene clustering, protein fusion events, phylogenetic co-occurrence profiles, and the genomic inference of metabolic regulons, are highly efficient methods for elucidation of novel sugar catabolic pathways. "
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    • "Nonetheless, DNA binding sites for SusR remained uncharacterized. Based on our previous analyses of DNA binding motifs of regulators from several TF families [21,31-33], we proposed that binding motifs for homologous SusR-like regulators in Bacteroides may appear similar to each other. Thus, for prediction of SusR regulatory motifs we used the following pipeline: (1) genes known or predicted to be co-regulated by SusR-like proteins were selected by genome context analysis in all Bacteroides genomes, (2) conserved DNA motifs were predicted in upstream regions of candidate co-regulated operons using a phylogenetic footprinting approach, and (3) the identified motifs were compared to each other and assigned to SusR-like regulators. "
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