Prevalence of SOS-mediated control of integron integrase expression as an adaptive trait of chromosomal and mobile integrons

Background: Integrons are found in hundreds of environmental bacterial species, but are mainly known as the agents responsible for the capture and spread of antibiotic-resistance determinants between Gram-negative pathogens. The SOS response is a regulatory network under control of the repressor protein LexA targeted at addressing DNA damage, thus promoting genetic variation in times of stress. We recently reported a direct link between the SOS response and the expression of integron integrases in Vibrio cholerae and a plasmid-borne class 1 mobile integron. SOS regulation enhances cassette swapping and capture in stressful conditions, while freezing the integron in steady environments. We conducted a systematic study of available integron integrase promoter sequences to analyze the extent of this relationship across the Bacteria domain. Results: Our results showed that LexA controls the expression of a large fraction of integron integrases by binding to Escherichia coli-like LexA binding sites. In addition, the results provide experimental validation of LexA control of the integrase gene for another Vibrio chromosomal integron and for a multiresistance plasmid harboring two integrons. There was a significant correlation between lack of LexA control and predicted inactivation of integrase genes, even though experimental evidence also indicates that LexA regulation may be lost to enhance expression of integron cassettes. Conclusions: Ancestral-state reconstruction on an integron integrase phylogeny led us to conclude that the ancestral integron was already regulated by LexA. The data also indicated that SOS regulation has been actively preserved in mobile integrons and large chromosomal integrons, suggesting that unregulated integrase activity is selected against. Nonetheless, additional adaptations have probably arisen to cope with unregulated integrase activity. Identifying them may be fundamental in deciphering the uneven distribution of integrons in the Bacteria domain

The SOS response controls integron recombination

Integrons are found in the genome of hundreds of environmental bacteria but are mainly known for their role in the capture and spread of antibiotic resistance determinants among Gram-negative pathogens. We report a direct link between this system and the ubiquitous SOS response. We found that LexA controlled expression of most integron integrases and consequently regulated cassette recombination. This regulatory coupling enhanced the potential for cassette swapping and capture in cells under stress, while minimizing cassette rearrangements or loss in constant environments. This finding exposes integrons as integrated adaptive systems and has implications for antibiotic treatment policie

Intégration de données pour l'analyse de transcriptome (mise en œuvre par l'entrepôt GEDAW (Gene Expression Data Warehouse))

L'intégration de données en bioinformatique est devenue essentielle à l'exploitation des masses de données engendrées par les avancées de la génomique. D'autre part, l'interprétation des données générées par les technologies d'étude de transcriptome nécessite une confrontation de données complémentaires sur les gènes étudiés ainsi que des moyens d'analyses puissants. Dans ce contexte, nous avons développé une approche d'intégration dédiée à l'analyse de transcriptome. GEDAW (Gene Expression DAta Warehouse) est un entrepôt de données orienté objet qui intègre une variété de sources et de standards des domaines de la génomique, de la biologie et de la médecine. Les données intégrées sont ensuite consultées et analysées afin d'extraire de la connaissance sur les données d'expression. GEDAW a été utilisé dans le contexte de l'étude du transcriptome hépatique, et a permis de dégager de nouvelles hypothèses quant à l'association de gènes avec des pathologies hépatiques.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Integrating and Warehousing Liver Gene Expression Data and Related Biomedical Resources in GEDAW

International audienceResearchers at the medical research institute Inserm U522 1 , specialized in the liver, use high throughput technologies to diagnose liver disease states. They seek to identify the set of dysregulated genes in different physiopa-thological situations, along with the molecular regulation mechanisms involved in the occurrence of these diseases, leading at mid-term to new diagnostic and therapeutic tools. To be able to resolve such a complex question, one has to consider both data generated on the genes by in-house transcriptome experiments and annotations extracted from the many publicly available heterogeneous resources in Biomedicine. This paper presents GEDAW, a gene expression data warehouse that has been developed to assist such discovery processes. The distinctive feature of GEDAW is that it systematically integrates gene information from a multitude of structured data sources. Data sources include: i) XML records of GENBANK to annotate gene sequence features, integrated using a schema mapping approach, ii) an inhouse relational database that stores detailed experimental data on the liver genes and is a permanent source for providing expression levels to the warehouse without unnecessary details on the experiments , and iii) a semi-structured data source called BioMeKE-XML that provides for each gene its nomenclature, its functional annotation according to Gene Ontology, and its medical annotation according to the UMLS. Because GEDAW is a liver gene expression data warehouse, we have paid more attention to the medical knowledge to be able to correlate biology mechanisms and medical knowledge with experimental data. The paper discusses the data sources and the transformation process that is applied to resolve syntactic and semantic conflicts between the source format and the GEDAW schema

Exploration of fMRI brain responses to oral sucrose after Roux-en-Y gastric bypass in obese yucatan minipigs in relationship with microbiota and metabolomics profiles

International audienceBackground & aimsIn most cases, Roux-en-Y gastric bypass (RYGBP) is an efficient intervention to lose weight, change eating behavior and improve metabolic outcomes in obese patients. We hypothesized that weight loss induced by RYGBP in obese Yucatan minipigs would induce specific modifications of the gut–brain axis and neurocognitive responses to oral sucrose stimulation in relationship with food intake control.MethodsAn integrative study was performed after SHAM (n = 8) or RYGBP (n = 8) surgery to disentangle the physiological, metabolic and neurocognitive mechanisms of RYGBP. BOLD fMRI responses to sucrose stimulations at different concentrations, brain mRNA expression, cecal microbiota, and plasma metabolomics were explored 4 months after surgery and integrated with WGCNA analysis.ResultsWe showed that weight loss induced by RYGBP or SHAM modulated differently the frontostriatal responses to oral sucrose stimulation, suggesting a different hedonic treatment and inhibitory control related to palatable food after RYGBP. The expression of brain genes involved in the serotoninergic and cannabinoid systems were impacted by RYGBP. Cecal microbiota was deeply modified and many metabolite features were differentially increased in RYGBP. Data integration with WGCNA identified interactions between key drivers of OTUs and metabolites features linked to RYGBP.ConclusionThis longitudinal study in the obese minipig model illustrates with a systemic and integrative analysis the mid-term consequences of RYGBP on brain mRNA expression, cecal microbiota and plasma metabolites. We confirmed the impact of RYGBP on functional brain responses related to food reward, hedonic evaluation and inhibitory control, which are key factors for the success of anti-obesity therapy and weight loss maintenance

Prevalence of SOS-mediated control of integron integrase expression as an adaptive trait of chromosomal and mobile integrons

Background: Integrons are found in hundreds of environmental bacterial species, but are mainly known as the agents responsible for the capture and spread of antibiotic-resistance determinants between Gram-negative pathogens. The SOS response is a regulatory network under control of the repressor protein LexA targeted at addressing DNA damage, thus promoting genetic variation in times of stress. We recently reported a direct link between the SOS response and the expression of integron integrases in Vibrio cholerae and a plasmid-borne class 1 mobile integron. SOS regulation enhances cassette swapping and capture in stressful conditions, while freezing the integron in steady environments. We conducted a systematic study of available integron integrase promoter sequences to analyze the extent of this relationship across the Bacteria domain. Results: Our results showed that LexA controls the expression of a large fraction of integron integrases by binding to Escherichia coli-like LexA binding sites. In addition, the results provide experimental validation of LexA control of the integrase gene for another Vibrio chromosomal integron and for a multiresistance plasmid harboring two integrons. There was a significant correlation between lack of LexA control and predicted inactivation of integrase genes, even though experimental evidence also indicates that LexA regulation may be lost to enhance expression of integron cassettes. Conclusions: Ancestral-state reconstruction on an integron integrase phylogeny led us to conclude that the ancestral integron was already regulated by LexA. The data also indicated that SOS regulation has been actively preserved in mobile integrons and large chromosomal integrons, suggesting that unregulated integrase activity is selected against. Nonetheless, additional adaptations have probably arisen to cope with unregulated integrase activity. Identifying them may be fundamental in deciphering the uneven distribution of integrons in the Bacteria domain