(Epi)genetic Inheritance in Schistosoma mansoni: A Systems Approach

International audienceThe G×E concept, in which genotype × environment interactions bring about the phenotype, is widely used to describe biological phenomena. We propose to extend the initial notion of the concept, replacing G by ‘inheritance system’. This system, comprised of both genome and epigenome components, collectively interacts with the environment to shape the development of a phenotype. In the case of the human blood fluke Schistosoma mansoni, responsible for intestinal bilharzia, the phenotypic trait that is most relevant to global health is infection success. Taking a systems biology view we show how genetic and epigenetic interactions result in ephemeral, but also heritable, phenotypic variations that are important for infection success

Chromatin structure changes around satellite repeats on the Schistosoma mansoni female sex chromosome suggest a possible mechanism for sex chromosome emergence.

International audienceBACKGROUND: In the leuphotrochozoan parasitic platyhelminth Schistosoma mansoni, male individuals are homogametic (ZZ) whereas females are heterogametic (ZW). To elucidate the mechanisms that led to the emergence of sex chromosomes we compared the genomic sequence and the chromatin structure of male and female individuals. As for many eukaryotes, the lower estimate for the repeat content is 40%, with an unknown proportion of domesticated repeats. We used massive sequencing to de novo assemble all repeats, and identify unambiguously Z-specific, W-specific and pseudoautosomal regions of the S. mansoni sex chromosomes.RESULTS: We show that 70-90 % of S. mansoni W and Z are pseudoautosomal. No female specific gene could be identified. Instead, the W-specific region is composed almost entirely of 36 satellite repeat families, of which 33 were previously unknown. Transcription and chromatin status of female specific repeats are stage specific: for those repeats that are transcribed, transcription is restricted to the larval stages lacking sexual dimorphism. In contrast, in the sexually dimorphic adult stage of the life cycle, no transcription occurs. In addition, the euchromatic character of histone modifications around the W-specific repeats decreases during the life cycle. Recombination repression occurs in this region even if homologous sequences are present on both the Z and W chromosomes.CONCLUSION: Our study provides for the first time evidence for the hypothesis that, at least in organisms with a ZW type of sex chromosomes, repeat-induced chromatin structure changes could indeed be the initial event in sex chromosome emergence

Chromatin structural changes around satellite repeats on the female sex chromosome in Schistosoma mansoni and their possible role in sex chromosome emergence

Background: In the leuphotrochozoan parasitic platyhelminth Schistosoma mansoni, male individuals are homogametic (ZZ) whereas females are heterogametic (ZW). To elucidate the mechanisms that led to the emergence of sex chromosomes, we compared the genomic sequence and the chromatin structure of male and female individuals. As for many eukaryotes, the lower estimate for the repeat content is 40%, with an unknown proportion of domesticated repeats. We used massive sequencing to de novo assemble all repeats, and identify unambiguously Z-specific, W-specific and pseudoautosomal regions of the S. mansoni sex chromosomes. Results: We show that 70 to 90% of S. mansoni W and Z are pseudoautosomal. No female-specific gene could be identified. Instead, the W-specific region is composed almost entirely of 36 satellite repeat families, of which 33 were previously unknown. Transcription and chromatin status of female-specific repeats are stage-specific: for those repeats that are transcribed, transcription is restricted to the larval stages lacking sexual dimorphism. In contrast, in the sexually dimorphic adult stage of the life cycle, no transcription occurs. In addition, the euchromatic character of histone modifications around the W-specific repeats decreases during the life cycle. Recombination repression occurs in this region even if homologous sequences are present on both the Z and W chromosomes. Conclusion: Our study provides for the first time evidence for the hypothesis that, at least in organisms with a ZW type of sex chromosomes, repeat-induced chromatin structure changes could indeed be the initial event in sex chromosome emergence.Keywords: Evolution, Dicer, Biomphalaria glabrata, Heterochromatin, Separate sexes, Argonaute Proteins, Y chromosomes, Genome, Repetitive DNA, Methylatio

Thermal Stress Triggers Broad Pocillopora damicornis Transcriptomic Remodeling, while Vibrio coralliilyticus Infection Induces a More Targeted Immuno-Suppression Response

Global change and its associated temperature increase has directly or indirectly changed the distributions of hosts and pathogens, and has affected host immunity, pathogen virulence and growth rates. This has resulted in increased disease in natural plant and animal populations worldwide, including scleractinian corals. While the effects of temperature increase on immunity and pathogen virulence have been clearly identified, their interaction, synergy and relative weight during pathogenesis remain poorly documented. We investigated these phenomena in the interaction between the coral Pocillopora damicornis and the bacterium Vibrio coralliilyticus, for which the infection process is temperature-dependent. We developed an experimental model that enabled unraveling the effects of thermal stress, and virulence vs. non-virulence of the bacterium. The physiological impacts of various treatments were quantified at the transcriptome level using a combination of RNA sequencing and targeted approaches. The results showed that thermal stress triggered a general weakening of the coral, making it more prone to infection, non-virulent bacterium induced an ‘efficient’ immune response, whereas virulent bacterium caused immuno-suppression in its host

The Human Cathelicidin LL-37 Preferentially Promotes Apoptosis of Infected Airway Epithelium

Cationic host defense peptides are key, evolutionarily conserved components of the innate immune system. The human cathelicidin LL-37 is an important cationic host defense peptide up-regulated in infection and inflammation, specifically in the human lung, and was shown to enhance the pulmonary clearance of the opportunistic pathogen Pseudomonas aeruginosa in vivo by as yet undefined mechanisms. In addition to its direct microbicidal potential, LL-37 can modulate inflammation and immune mechanisms in host defense against infection, including the capacity to modulate cell death pathways. We demonstrate that at physiologically relevant concentrations of LL-37, this peptide preferentially promoted the apoptosis of infected airway epithelium, via enhanced LL-37-induced mitochondrial membrane depolarization and release of cytochrome c, with activation of caspase-9 and caspase-3 and induction of apoptosis, which only occurred in the presence of both peptide and bacteria, but not with either stimulus alone. This synergistic induction of apoptosis in infected cells was caspase-dependent, contrasting with the caspase-independent cell death induced by supraphysiologic levels of peptide alone. We demonstrate that the synergistic induction of apoptosis by LL-37 and Pseudomonas aeruginosa required specific bacteria-epithelial cell interactions with whole, live bacteria, and bacterial invasion of the epithelial cell. We propose that the LL-37-mediated apoptosis of infected, compromised airway epithelial cells may represent a novel inflammomodulatory role for this peptide in innate host defense, promoting the clearance of respiratory pathogens

Genomics of the ccoNOQP -encoded cbb 3 oxidase complex in bacteria

International audienceMany bacteria adapt to microoxic conditions by synthesizing a particular cytochrome c oxidase (cbb 3) complex with a high affinity for O2, encoded by the ccoNOQP operon. A survey of genome databases indicates that ccoNOQP sequences are widespread in all sub-branches of Proteobacteria but otherwise are found only in bacteria of the CFB group (Cytophaga, Flexibacter, Bacteroides). Our analysis of available genome sequences suggests four major strategies of regulating ccoNOQP expression in response to O2. The most widespread strategy involves direct regulation by the O2-responsive protein Fnr. The second strategy involves an O2-insensitive paralogue of Fnr, FixK, whose expression is regulated by the O2-responding FixLJ two-component system. A third strategy of mixed regulation operates in bacteria carrying both fnr and fixLJ-fixK genes. Another, not yet identified, strategy is likely to operate in the ε-Proteobacteria Helicobacter pylori and Campylobacter jejuni which lack fnr and fixLJ-fixK genes. The FixLJ strategy appears specific for the α-subclass of Proteobacteria but is not restricted to rhizobia in which it was originally discovered

Host Defense Peptides in the Oral Cavity

International audienceHost defense peptides (HDPs) are important in defense of tissues throughout the human mouth. Like resident microbial populations, HDPs are diverse, species-specific, and site-specific, and they have evolved in response to selection pressures exerted by resident and pathogenic microbial populations. Their site-specific expression is likely to be a significant contributor to the tissue tropism displayed by microorganisms throughout the body. Currently there is an impetus to understand host–microbe interactions in health as well as disease, and the mechanisms underlying the ability of host tissues to tolerate resident microbial populations while maintaining efficient responses to pathogens are of fundamental importance. No consistent correlation has emerged so far between oral commensalism and susceptibility to, or induction of HDPs. Equally; pathogenic bacteria exhibit a variety of strategies for evading or surviving HDPs. However, only a small number of oral commensal species and strains have been studied. Also, to truly understand the in vivo roles of HDPs in health and protection against infection one needs to understand their interactions with organisms in complex biofilm communities, not with planktonic monocultures as has predominantly been the case to date

The FixM Flavoprotein Modulates Inhibition by AICAR or 5′AMP of Respiratory and Nitrogen Fixation Gene Expression in Sinorhizobium meliloti

International audienceAICAR, a purine-related metabolite, was recently shown to inhibit respiratory and nifA gene expression in Sinorhizobium meliloti. Here, we demonstrate that AICAR has essentially no or little effect in a wild-type S. meliloti strain and inhibits respiratory and nitrogen fixation gene expression only in specific mutant backgrounds. We have analyzed in detail a mutant in which addition of AICAR inhibited fixK, fixN, fixT, and nifA expression. The corresponding gene, fixM, is located just downstream of fixK 1 on pSymA megaplasmid and encodes a flavoprotein oxidore-ductase. 5′AMP, a structural analogue of AICAR, mimicked AICAR effect as well as the nucleoside precursors AICAriboside and adenosine. The mode of action of AICAR and 5′AMP in vivo was investigated. We demonstrate that AICAR does not affect FixK transcriptional activity and instead regulates fixK and nifA gene expression. We hypothesize that AICAR and 5′AMP may modulate, possibly indirectly, the activity of the FixLJ two-component regulatory system. The possible physiological roles of AICAR, 5′AMP, and fixM in the context of symbiosis are discussed

An epigenetic molluscicide

Biomphalaria glabrata is a freshwater mollusk that serves as obligatory intermediate host to Schistosoma mansoni, agent of the neglected tropical disease schistosomiasis that affects roughly 250 Mio people. One of the ways to control the pathogenic agent is to interrupt the life cycle by eliminating the intermediate snail host though foal treatment of water bodies with molluscicides. Currently recommended molluscicides were developed in the 1950ths and lack sufficient specificity, e.g., they are toxic to fish. To provide new lead compounds for the development of a new type of molluscicides we used a rational approach based on the hypotheses that interfering with an important epigenetic mark, DNA methylation, would impede development of the snail host. We present here the compound 29, analogues-based compound that mimic substrates of DNA methyltransferases. We show that compound 29 has (i) low cytotoxicity for human cells, (ii) it inhibits DNA methylation, and (iii) it decreases fecundity in B.glabrata. It is therefore conceivable to produce compounds that act as specific epigenetic molluscicides