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Comprehensive computational analysis of bacterial CRP/FNR superfamily and its target motifs reveals stepwise evolution of transcriptional networks.

ABSTRACT: The cAMP receptor protein (CRP)/fumarate and nitrate reduction regulatory protein (FNR)-type transcription factors (TFs) are members of a well-characterized global TF family in bacteria and have two conserved domains: the N-terminal ligand-binding domain for small molecules (e.g., cAMP, NO, or O(2)) and the C-terminal DNA-binding domain. Although the CRP/FNR-type TFs recognize very similar consensus DNA target sequences, they can regulate different sets of genes in response to environmental signals. To clarify the evolution of the CRP/FNR-type TFs throughout the bacterial kingdom, we undertook a comprehensive computational analysis of a large number of annotated CRP/FNR-type TFs and the corresponding bacterial genomes. Based on the amino acid sequence similarities among 1,455 annotated CRP/FNR-type TFs, spectral clustering classified the TFs into 12 representative groups, and stepwise clustering allowed us to propose a possible process of protein evolution. Although each cluster mainly consists of functionally distinct members (e.g., CRP, NTC, FNR-like protein, and FixK), FNR-related TFs are found in several groups and are distributed in a wide range of bacterial phyla in the sequence similarity network. This result suggests that the CRP/FNR-type TFs originated from an ancestral FNR protein, involved in nitrogen fixation. Furthermore, a phylogenetic profiling analysis showed that combinations of TFs and their target genes have fluctuated dynamically during bacterial evolution. A genome-wide analysis of TF-binding sites also suggested that the diversity of the transcriptional regulatory system was derived by the stepwise adaptation of TF-binding sites to the evolution of TFs.

SUBMITTER: Matsui M

PROVIDER: S-EPMC3590769 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Comprehensive computational analysis of bacterial CRP/FNR superfamily and its target motifs reveals stepwise evolution of transcriptional networks.

Matsui Motomu M Tomita Masaru M Kanai Akio A

Genome biology and evolution 20130101 2

The cAMP receptor protein (CRP)/fumarate and nitrate reduction regulatory protein (FNR)-type transcription factors (TFs) are members of a well-characterized global TF family in bacteria and have two conserved domains: the N-terminal ligand-binding domain for small molecules (e.g., cAMP, NO, or O(2)) and the C-terminal DNA-binding domain. Although the CRP/FNR-type TFs recognize very similar consensus DNA target sequences, they can regulate different sets of genes in response to environmental sign ...[more]

PMID: 23315382

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Project description:Phylogenetic and sequence similarity network analyses of the CRP (cyclic AMP receptor protein)/FNR (fumarate and nitrate reductase regulatory protein) family of transcription factors indicate the presence of numerous subgroups, many of which have not been analyzed. Five homologs of the CRP/FNR family are present in the Rhodobacter capsulatus genome. One is a member of a broadly disseminated, previously uncharacterized CRP/FNR family subgroup encoded by the gene rcc01561. In this study, we utilize mutational disruption, transcriptome sequencing (RNA-seq), and chromatin immunoprecipitation sequencing (ChIP-seq) to determine the role of RCC01561 in regulating R. capsulatus physiology. This analysis shows that a mutant strain disrupted for rcc01561 exhibits altered expression of 451 genes anaerobically. A detailed analysis of the affected loci shows that RCC01561 represses photosynthesis and favors catabolism over anabolism and the use of the Entner-Doudoroff shunt and glycolysis over that of the tricarboxylic acid (TCA) cycle to limit NADH and ATP formation. This newly characterized CRP/FNR family member with a predominant role in reducing the production of reducing potential and ATP is given the nomenclature RedB as it functions as an energy and redox brake. Beyond limiting energy production, RedB also represses the expression of numerous genes involved in protein synthesis, including those involved in translation initiation, tRNA synthesis and charging, and amino acid biosynthesis. IMPORTANCE CRP and FNR are well-characterized members of the CRP/FNR family of regulatory proteins that function to maximize cellular energy production. In this study, we identify several new subgroups of the CRP/FNR family, many of which have not yet been characterized. Using Rhodobacter capsulatus as a model, we have mutationally disrupted the gene rcc01561, which codes for a transcription factor that is a member of a unique subgroup of the CRP/FNR family. Transcriptomic analysis shows that the disruption of rcc01561 leads to the altered expression of 451 genes anaerobically. Analysis of these regulated genes indicates that RCC01561 has a novel role in limiting cellular energy production. To our knowledge, this is first example of a member of the CRP/FNR family that functions as a brake on cellular energy production.

Project description:Microorganisms must respond to environmental changes to survive, often by controlling transcription initiation. Intermittent aeration during wastewater treatment presents a cyclically changing environment to which microorganisms must react. We used an intermittently aerated bioreactor performing partial nitritation and anammox (PNA) to investigate how the microbiome responds to recurring change. Meta-transcriptomic analysis revealed a dramatic disconnect between the relative DNA abundance and gene expression within the metagenome-assembled genomes (MAGs) of community members, suggesting the importance of transcriptional regulation in this microbiome. To explore how community members responded to cyclic aeration via transcriptional regulation, we searched for homologs of the catabolite repressor protein/fumarate and nitrate reductase regulatory protein (CRP/FNR) family of transcription factors (TFs) within the MAGs. Using phylogenetic analyses, evaluation of sequence conservation in important amino acid residues, and prediction of genes regulated by TFs in the MAGs, we identified homologs of the oxygen-sensing FNR in Nitrosomonas and Rhodocyclaceae, nitrogen-sensing dissimilative nitrate respiration regulator that responds to nitrogen species (DNR) in Rhodocyclaceae, and nitrogen-sensing nitrite and nitric oxide reductase regulator that responds to nitrogen species (NnrR) in Nitrospira MAGs. Our data also predict that CRP/FNR homologs in Ignavibacteria, Flavobacteriales, and Saprospiraceae MAGs sense carbon availability. In addition, a CRP/FNR homolog in a Brocadia MAG was most closely related to CRP TFs known to sense carbon sources in well-studied organisms. However, we predict that in autotrophic Brocadia, this TF most likely regulates a diverse set of functions, including a response to stress during the cyclic aerobic/anoxic conditions. Overall, this analysis allowed us to define a meta-regulon of the PNA microbiome that explains functions and interactions of the most active community members. IMPORTANCE Microbiomes are important contributors to many ecosystems, including ones where nutrient cycling is stimulated by aeration control. Optimizing cyclic aeration helps reduce energy needs and maximize microbiome performance during wastewater treatment; however, little is known about how most microbial community members respond to these alternating conditions. We defined the meta-regulon of a PNA microbiome by combining existing knowledge of how the CRP/FNR family of bacterial TFs respond to stimuli, with metatranscriptomic analyses to characterize gene expression changes during aeration cycles. Our results indicated that, for some members of the community, prior knowledge is sufficient for high-confidence assignments of TF function, whereas other community members have CRP/FNR TFs for which inferences of function are limited by lack of prior knowledge. This study provides a framework to begin elucidating meta-regulons in microbiomes, where pure cultures are not available for traditional transcriptional regulation studies. Defining the meta-regulon can help in optimizing microbiome performance.

Dataset Information

Comprehensive computational analysis of bacterial CRP/FNR superfamily and its target motifs reveals stepwise evolution of transcriptional networks.

Publications

Comprehensive computational analysis of bacterial CRP/FNR superfamily and its target motifs reveals stepwise evolution of transcriptional networks.

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