DNA supercoiling acts as a global and ancestral regulator of bacterial gene expression. In this review, we advocate that it plays a pivotal role in host-pathogen interactions by transducing environmental signals to the bacterial chromosome and coordinating its transcriptional response. We present available evidence that DNA supercoiling is modulated by environmental stress conditions relevant to the infection process according to ancestral mechanisms, in zoopathogens as well as phytopathogens. We review the results of transcriptomics studies obtained in widely distant bacterial species, showing that such structural transitions of the chromosome are associated to a complex transcriptional response affecting a large fraction of the genome. Mechanisms and computational models of the transcriptional regulation by DNA supercoiling are then discussed, involving both basal interactions of RNA Polymerase with promoter DNA, and more specific interactions with regulatory proteins. A final part is specifically focused on the regulation of virulence genes within pathogenicity islands of several pathogenic bacterial species.
DNA supercoiling acts as a global transcriptional regulator in bacteria, that plays an important role in adapting their expression programme to environmental changes, but for which no quantitative or even qualitative regulatory model is available. Here, we focus on spatial supercoiling heterogeneities caused by the transcription process itself, which strongly contribute to this regulation mode. We propose a new mechanistic modeling of the transcription-supercoiling dynamical coupling along a genome, which allows simulating and quantitatively reproducing in vitro and in vivo transcription assays, and highlights the role of genes’ local orientation in their supercoiling sensitivity. Consistently with predictions, we show that chromosomal relaxation artificially induced by gyrase inhibitors selectively activates convergent genes in several enterobacteria, while conversely, an increase in DNA supercoiling naturally selected in a long-term evolution experiment with Escherichia coli favours divergent genes. Simulations show that these global expression responses to changes in DNA supercoiling result from fundamental mechanical constraints imposed by transcription, independently from more specific regulation of each promoter. These constraints underpin a significant and predictable contribution to the complex rules by which bacteria use DNA supercoiling as a global but fine-tuned transcriptional regulator.
Figure 1: Shifted effective promoter activation curve used to simulate the data of Chong et al. [1] (Fig. 2B). This modified curve accounts for the stalling effect of positive supercoils on transcription elongation in this in vitro experiment in absence of DNA gyrase, and is consistent with the observed repressive effect of positive supercoils.Figure 2: Reversed promoter activation curve used for the gyrA promoter (Fig. 3B), which is a very specific promoter activated by DNA relaxation to ensure an homeostasis of the SC level in the cell [2].
In this study, we highlight the role of the discriminator as a global sensor of supercoiling variations and propose the first quantitative regulatory model of this principle, based on the specific step of promoter opening during transcription initiation. It defines the predictive rule by which SC quantitatively modulates the expression rate of bacterial promoters, depending on the G/C content of their discriminator and independently from promoter-specific regulatory proteins.
Bacterial pathogenic growth requires a swift coordination of pathogenicity function with various kinds of environmental stress encountered in the course of host infection. Among the factors critical for bacterial adaptation are changes of DNA topology and binding effects of nucleoid-associated proteins transducing the environmental signals to the chromosome and coordinating the global transcriptional response to stress. In this study, we use the model phytopathogen Dickeya dadantii to analyse the organisation of transcription by the nucleoid-associated heterodimeric protein IHF. We inactivated the IHFα subunit of IHF thus precluding the IHFαβ heterodimer formation and determined both phenotypic effects of ihfA mutation on D. dadantii virulence and the transcriptional response under various conditions of growth. We show that ihfA mutation reorganises the genomic expression by modulating the distribution of chromosomal DNA supercoils at different length scales, thus affecting many virulence genes involved in both symptomatic and asymptomatic phases of infection, including those required for pectin catabolism. Altogether, we propose that IHF heterodimer is a ‘transcriptional domainin’ protein, the lack of which impairs the spatiotemporal organisation of transcriptional stress-response domains harbouring various virulence traits, thus abrogating the pathogenicity of D. dadantii.
Recent studies strongly suggest that in bacteria, both the genomic pattern of DNA thermodynamic stability and the order of genes along the chromosomal origin-to-terminus axis are highly conserved and that this spatial organization plays a crucial role in coordinating genomic transcription. In this article, we explore the relationship between genomic sequence organization and transcription in the commensal bacterium Escherichia coli and the plant pathogen Dickeya. We argue that, while in E. coli the gradient of DNA thermodynamic stability and gene order along the origin-to-terminus axis represent major organizational features orchestrating temporal gene expression, the genomic sequence organization of Dickeya is more complex, demonstrating extended chromosomal domains of thermodynamically distinct DNA sequences eliciting specific transcriptional responses to various kinds of stress encountered during pathogenic growth. This feature of the Dickeya genome is likely an adaptation to the pathogenic lifestyle utilizing differences in genomic sequence organization for the selective expression of virulence traits. We propose that the coupling of DNA thermodynamic stability and genetic function provides a common organizational principle for the coordinated expression of genes during both normal and pathogenic bacterial growth.
Synapses are highly specialized structures that interconnect neurons to form functional networks dedicated to neuronal communication. During brain development, synapses undergo activity-dependent rearrangements leading to both structural and functional changes. Many molecular processes are involved in this regulation, including post-translational modifications by the Small Ubiquitin-like MOdifier SUMO. To get a wider view of the panel of endogenous synaptic SUMO-modified proteins in the mammalian brain, we combined subcellular fractionation of rat brains at the post-natal day 14 with denaturing immunoprecipitation using SUMO2/3 antibodies and tandem mass spectrometry analysis. Our screening identified 803 candidate SUMO2/3 targets, which represents about 18% of the synaptic proteome. Our dataset includes neurotransmitter receptors, transporters, adhesion molecules, scaffolding proteins as well as vesicular trafficking and cytoskeleton-associated proteins, defining SUMO2/3 as a central regulator of the synaptic organization and function.
This is the first transcriptomic map of a
Dickeya
species. It may therefore significantly contribute to further progress in the field of phytopathogenicity.
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