Pathogenic adaptation of intracellular bacteria by rewiring a cis-regulatory input function.
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ABSTRACT:
SUBMITTER: Osborne SE
PROVIDER: S-EPMC2645909 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The transcription rate of a gene is often controlled by several regulators that bind specific sites in the gene's cis-regulatory region. The combined effect of these regulators is described by a cis-regulatory input function. What determines the form of an input function, and how variable is it with respect to mutations? To address this, we employ the well-characterized lac operon of Escherichia coli, which has an elaborate input function, intermediate between Boolean AND-gate and OR-gate logic. We mapped in detail the input function of 12 variants of the lac promoter, each with different point mutations in the regulator binding sites, by means of accurate expression measurements from living cells. We find that even a few mutations can significantly change the input function, resulting in functions that resemble Pure AND gates, OR gates, or single-input switches. Other types of gates were not found. The variant input functions can be described in a unified manner by a mathematical model. The model also lets us predict which functions cannot be reached by point mutations. The input function that we studied thus appears to be plastic, in the sense that many of the mutations do not ruin the regulation completely but rather result in new ways to integrate the inputs.
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Project description:A coregulated module of genes ("regulon") can have evolutionarily conserved expression patterns and yet have diverged upstream regulators across species. For instance, the ribosomal genes regulon is regulated by the transcription factor (TF) TBF1 in Candida albicans, while in Saccharomyces cerevisiae it is regulated by RAP1. Only a handful of such rewiring events have been established, and the prevalence or conditions conducive to such events are not well known. Here, we develop a novel probabilistic scoring method to comprehensively screen for regulatory rewiring within regulons across 23 yeast species. Investigation of 1,713 regulons and 176 TFs yielded 5,353 significant rewiring events at 5% false discovery rate (FDR). Besides successfully recapitulating known rewiring events, our analyses also suggest TF candidates for certain processes reported to be under distinct regulatory controls in S. cerevisiae and C. albicans, for which the implied regulators are not known: 1) Oxidative stress response (Sc-MSN2 to Ca-FKH2) and 2) nutrient modulation (Sc-RTG1 to Ca-GCN4/Ca-UME6). Furthermore, a stringent screen to detect TF rewiring at individual genes identified 1,446 events at 10% FDR. Overall, these events are supported by strong coexpression between the predicted regulator and its target gene(s) in a species-specific fashion (>50-fold). Independent functional analyses of rewiring TF pairs revealed greater functional interactions and shared biological processes between them (P = 1 × 10(-3)).Our study represents the first comprehensive assessment of regulatory rewiring; with a novel approach that has generated a unique high-confidence resource of several specific events, suggesting that evolutionary rewiring is relatively frequent and may be a significant mechanism of regulatory innovation.
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Project description:Understanding the mechanisms that generate variation is a common pursuit unifying the life sciences. Bacteria represent an especially striking puzzle, because closely related strains possess radically different metabolic and ecological capabilities. Differences in protein repertoire arising from gene transfer are currently considered the primary mechanism underlying phenotypic plasticity in bacteria. Although bacterial coding plasticity has been extensively studied in previous decades, little is known about the role that regulatory plasticity plays in bacterial evolution. Here, we show that bacterial genes can rapidly shift between multiple regulatory modes by acquiring functionally divergent nonhomologous promoter regions. Through analysis of 270,000 regulatory regions across 247 genomes, we demonstrate that regulatory "switching" to nonhomologous alternatives is ubiquitous, occurring across the bacterial domain. Using comparative transcriptomics, we show that at least 16% of the expression divergence between Escherichia coli strains can be explained by this regulatory switching. Further, using an oligonucleotide regulatory library, we establish that switching affects bacterial promoter architecture. We provide evidence that regulatory switching can occur through horizontal regulatory transfer, which allows regulatory regions to move across strains, and even genera, independently from the genes they regulate. Finally, by experimentally characterizing the fitness effect of a regulatory transfer on a pathogenic E. coli strain, we demonstrate that regulatory switching elicits important phenotypic consequences. Taken together, our findings expose previously unappreciated regulatory plasticity in bacteria and provide a gateway for understanding bacterial phenotypic variation and adaptation.
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Project description:The rapid pace of evolution in bacteria is widely attributed to the promiscuous horizontal transfer and recombination of protein-coding genes. However, it is not known whether the same forces also drive the evolution of non-coding regulatory regions. Here we demonstrate that regulatory region can M-bM-^@M-^XswitchM-bM-^@M-^Y between non-homologous alternatives and that such switching is ubiquitous, occurring across the bacterial domain. We show that such regulatory switching strongly impacts promoter architecture and expression divergence. We further show that regulatory transfer facilitates rapid phenotypic diversification of a human pathogen. This regulatory mobility enables bacterial genes to access a vast pool of potential regulatory elements, facilitating efficient exploration of the regulatory landscape. Examination of 2 E. coli strains in 2 conditions
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Project description:Oesophageal adenocarcinoma (OAC) patients show poor survival rates and there are few targeted molecular therapies available. However, components of the receptor tyrosine kinase (RTK) driven pathways are commonly mutated in OAC, typified by high frequency amplifications of the RTK ERBB2. ERBB2 can be therapeutically targeted, but this has limited clinical benefit due to the acquisition of drug resistance. Here we examined how OAC cells adapt to ERBB2 inhibition as they transition to a drug resistant state. ERBB2 inhibition triggers widespread remodelling of the accessible chromatin landscape and the underlying gene regulatory networks. The transcriptional regulators HNF4A and PPARGC1A play a key role in this network rewiring. Initially, inhibition of cell cycle associated gene expression programmes is observed, with compensatory increases in the programmes driving changes in metabolic activity. Both PPARGC1A and HNF4A are required for the acquisition of resistance to ERBB2 inhibition and PPARGC1A is instrumental in promoting a switch to dependency on oxidative phosphorylation. Our work therefore reveals the molecular pathways that support the acquisition of a resistant state and points to potential new therapeutic strategies to combat cellular adaptation and ensuing drug resistance.
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Project description:Transcriptional rewiring is the regulation of different target genes by orthologous regulators in different organisms. While this phenomenon has been observed, it has not been extensively studied, particularly in core regulatory systems. Several global cell cycle regulators are conserved in the Alphaproteobacteria, providing an excellent model to study this phenomenon. First characterized in Caulobacter crescentus, GcrA and CcrM compose a DNA methylation-based regulatory system that helps coordinate the complex life cycle of this organism. These regulators are well-conserved across Alphaproteobacteria, but the extent to which their regulatory targets are conserved is not known. In this study, the regulatory targets of GcrA and CcrM were analyzed by SMRT-seq, RNA-seq, and ChIP-seq technologies in the Alphaproteobacterium Brevundimonas subvibrioides, and then compared to those of its close relative C. crescentus that inhabits the same environment. Although the regulators themselves are highly conserved, the genes they regulate are vastly different. GcrA directly regulates 204 genes in C. crescentus, and though B. subvibrioides has orthologs to 147 of those genes, only 48 genes retained GcrA binding in their promoter regions. Additionally, only 12 of those 48 genes demonstrated significant transcriptional change in a gcrA mutant, suggesting extensive transcriptional rewiring between these organisms. Similarly, out of hundreds of genes CcrM regulates in each of these organisms, only 2 genes were found in common. When multiple Alphaproteobacterial genomes were analyzed bioinformatically for potential GcrA regulatory targets, the regulation of genes involved in DNA replication and cell division was well conserved across the Caulobacterales but not outside this order. This work suggests that significant transcriptional rewiring can occur in cell cycle regulatory systems even over short evolutionary distances.
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