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Abstract Epithelial cells are the first point of contact for bacteria entering the respiratory tract. Streptococcus pneumoniae is an obligate human pathobiont of the nasal mucosa, carried asymptomatically but also the cause of severe pneumoniae. The role of the epithelium in maintaining homeostatic interactions or mounting an inflammatory response to invasive S. pneumoniae is currently poorly understood. However, studies have shown that chromatin modifications, at the histone level, induced by bacterial pathogens interfere with the host transcriptional program and promote infection. Here, we uncover a histone modification induced by S. pneumoniae infection maintained for at least 9 days upon clearance of bacteria with antibiotics. Di-methylation of histone H3 on lysine 4 (H3K4me2) is induced in an active manner by bacterial attachment to host cells. We show that infection establishes a unique epigenetic program affecting the transcriptional response of epithelial cells, rendering them more permissive upon secondary infection. Our results establish H3K4me2 as a unique modification induced by infection, distinct from H3K4me3 or me1, which localizes to enhancer regions genome-wide. Therefore, this study reveals evidence that bacterial infection leaves a memory in epithelial cells after bacterial clearance, in an epigenomic mark, thereby altering cellular responses to subsequent infections and promoting infection.

Precision Medicine is being increasingly used in the developed world to improve health care. While several Precision Medicine (PM) initiatives have been launched worldwide, their implementations have proven to be more challenging particularly in low- and middle-income countries. To address this issue, the “Personalized Medicine in North Africa” initiative (PerMediNA) was launched in three North African countries namely Tunisia, Algeria and Morocco. PerMediNA is coordinated by Institut Pasteur de Tunis together with the French Ministry for Europe and Foreign Affairs, with the support of Institut Pasteur in France. The project is carried out along with Institut Pasteur d’Algérie and Institut Pasteur du Maroc in collaboration with national and international leading institutions in the field of PM including Institut Gustave Roussy in Paris. PerMediNA aims to assess the readiness level of PM implementation in North Africa, to strengthen PM infrastructure, to provide workforce training, to generate genomic data on North African populations, to implement cost effective, affordable and sustainable genetic testing for cancer patients and to inform policy makers on how to translate research knowledge into health products and services. Gender equity and involvement of young scientists in this implementation process are other key goals of the PerMediNA project.In this paper, we are describing PerMediNA as the first PM implementation initiative in North Africa. Such initiatives contribute significantly in shortening existing health disparities and inequities between developed and developing countries and accelerate access to innovative treatments for global health.

Virulence of the neonatal pathogen Group B Streptococcus is under the control of the master regulator CovR. Inactivation of CovR is associated with large-scale transcriptome remodeling and impairs almost every step of the interaction between the pathogen and the host. However, transcriptome analyses suggested a plasticity of the CovR signaling pathway in clinical isolates leading to phenotypic heterogeneity in the bacterial population. In this study, we characterized the CovR regulatory network in a strain representative of the CC-17 hypervirulent lineage responsible of the majority of neonatal meningitis. Transcriptome and genome-wide binding analysis reveal the architecture of the CovR network characterized by the direct repression of a large array of virulence-associated genes and the extent of co-regulation at specific loci. Comparative functional analysis of the signaling network links strain-specificities to the regulation of the pan-genome, including the two specific hypervirulent adhesins and horizontally acquired genes, to mutations in CovR-regulated promoters, and to variability in CovR activation by phosphorylation. This regulatory adaptation occurs at the level of genes, promoters, and of CovR itself, and allows to globally reshape the expression of virulence genes. Overall, our results reveal the direct, coordinated, and strain-specific regulation of virulence genes by the master regulator CovR and suggest that the intra-species evolution of the signaling network is as important as the expression of specific virulence factors in the emergence of clone associated with specific diseases.

Abstract Background Polycomb Repressive Complexes 2 (PRC2) are multi-protein chromatin modifiers that are evolutionarily conserved among eukaryotes and play key roles in the regulation of gene expression, notably through the trimethylation of lysine 27 of histone H3 (H3K27me3). Although PRC2-mediated gene regulation has been studied in many organisms, few studies have explored in depth the evolutionary conservation of PRC2 targets. Results Here, we compare the H3K27me3 epigenomic profiles for the two closely related species Arabidopsis thaliana and Arabidopsis lyrata and the more distant species Arabis alpina, three Brassicaceae that diverged from each other within the past 24 million years. Using a robust set of gene orthologs present in the three species, we identify two classes of evolutionarily conserved PRC2 targets, which are characterized by either developmentally plastic or developmentally constrained H3K27me3 marking across species. Constrained H3K27me3 marking is associated with higher conservation of promoter sequence information content and higher nucleosome occupancy compared to plastic H3K27me3 marking. Moreover, gene orthologs with constrained H3K27me3 marking exhibit a higher degree of tissue specificity and tend to be involved in developmental functions, whereas gene orthologs with plastic H3K27me3 marking preferentially encode proteins associated with metabolism and stress responses. In addition, gene orthologs with constrained H3K27me3 marking are the predominant contributors to higher-order chromosome organization. Conclusions Our findings indicate that developmentally plastic and constrained H3K27me3 marking define two evolutionarily conserved modes of PRC2-mediated gene regulation that are associated with distinct selective pressures operating at multiple scales, from DNA sequence to gene function and chromosome architecture.

SUPERFAMILIARASSe estima que la superfamilia Ras contiene 60 - 100 miembros que cumplen diferentesfunciones en el medio celular: transducción de señales (Ras), regulación del citoesque-leto (Rho), señalamiento vesicular (Rab) y regulación de la traducción (EF). Estas pro-teínas presentan una baja homología de secuencia, entre 35 y 55% (Quilliam et al.,1995), pero comparten un mismo patrón estructural (dominio G) relacionado a launión con GTP/GDP. La búsqueda de relaciones filogenéticas entre estas secuenciasapunta a comprender si sus diferencias representan fenómenos de divergencia o conver-gencia evolutiva. Otro tipo de estudios, centrados en el fenotipo proteico, buscan defi-nir el significado que los residuos conservados puedan tener en la definición de la es-tructura y la función de la proteína. El dominio G más estudiado corresponde al de lafamilia Ras en humanos, compuesta por tres proto-oncogenes: N-Ras, H-Ras y K-Ras.Éstas son proteínas de 170 a 189 residuos y 19 a 21 kDa, por lo cual se identifican conel nombre genérico de p21. Hay citosólicas y de membrana celular; las de membrana seunen a la hemicapa citosólica de la membrana celular, gracias al motivo Cis-A-A-X (A =residuo alifático, X = residuo no polar) que es agregado por modificación post-tradu-ccional. La transformación celular inducida por Ras es causada por su activación pro-longada ocasionada por:-Sobre-expresión: debido a la concentración limitada de las proteínas reguladorasGAP (GTPase activating protein).-Mutación puntual: En residuos 12, 13, 59, 61, 63porque conllevan un aumento de la actividad GTPasa.(Aquellas subrayadas corresponden a las mutaciones que ocurren naturalmente). En residuos 116, 119, 146, 156 porque producen una disminución de la afinidadpor el nucleótido fosfato y un aumento en el intercambio GDP/GTP, debido a lamayor concentración de este último en el citoplasma.

In the present study we analize the productivity of the dihybrid cross +//+ e//e x vg//vg +//+ and its reciprocal, carried on up to the second generation under different environmental conditions: two culture media (maize and banana) and two temperatures (23 and 26ºC). The differences were shown to be statistically significantfor the temperature in the first generation, the culture medium and the parental line in the second generation. At a general level, the significant factors were the temperature and the culture medium. Perhaps the genotipic effects caused by the parental line are balanced and masked, when considered at this level. The temperature of 26ºC and the culture media of maize showed always the best productivity.

CONSTRUCCLÓN DE UN HIPERCICLO: AXIOMAS, RESTRICCIONES Y SUPUESTOS BÁSICOS intentar una explicación sobre la aparición de las primeras secuencias proteicas implica la construcción de un escenario primitivo para el cual, se hace uso de "axiomas" de validez conocida y, justificar cada propuesta con base en las condiciones presentes o pasadas del sistema, relacionando edemas, las hipótesis planteadas con algunas evidencias actuales. Se parte de un primitivo mundo de RNA donde, superadas las restricciones de tamaño molecular y dada una diversidad estructural y funcional mínima, sería posible la existencia de hiperciclos suficientemente redundantes para evitar la catástrofe de error (Eigen eta!., 1980). Al interior de estos sistemas las moléculas serían seleccionadas por su eficiencia catalítica y su efecto sobre la capacidad de replicación del conjunto. Acorde con la tendencia hacia la optimización catalítica y aumento en complejidad, se explica la modificación del tamaño de los hiperciclos. Resultado de modificaciones al interior de la estructura y dinámica del hiperciclo, cambia el equilibrio establecido entre las presiones selectivas tendientes a incluir nuevas moléculas y aquellas dirigidas hacia la disminución de elementos. Es el caso de la inclusión de aminoácidos dentro del hiperciclo y la unión de las secuencias ribozirnáticas en unidades estructurales definidas.

BACKGROUND: Linear motifs are short modules of protein sequences that play a crucial role in mediating and regulating many protein-protein interactions. The function of linear motifs strongly depends on the context, e.g. functional instances mainly occur inside flexible regions that are accessible for interaction. Sometimes linear motifs appear as isolated islands of conservation in multiple sequence alignments. However, they also occur in larger blocks of sequence conservation, suggesting an active role for the neighbouring amino acids. RESULTS: The evolution of regions flanking 116 functional linear motif instances was studied. The conservation of the amino acid sequence and order/disorder tendency of those regions was related to presence/absence of the instance. For the majority of the analysed instances, the pairs of sequences conserving the linear motif were also observed to maintain a similar local structural tendency and/or to have higher local sequence conservation when compared to pairs of sequences where one is missing the linear motif. Furthermore, those instances have a higher chance to co-evolve with the neighbouring residues in comparison to the distant ones. Those findings are supported by examples where the regulation of the linear motif-mediated interaction has been shown to depend on the modifications (e.g. phosphorylation) at neighbouring positions or is thought to benefit from the binding versatility of disordered regions. CONCLUSION: The results suggest that flanking regions are relevant for linear motif-mediated interactions, both at the structural and sequence level. More interestingly, they indicate that the prediction of linear motif instances can be enriched with contextual information by performing a sequence analysis similar to the one presented here. This can facilitate the understanding of the role of these predicted instances in determining the protein function inside the broader context of the cellular network where they arise.

Motivation: KEN-box-mediated target selection is one of the mechanisms used in the proteasomal destruction of mitotic cell cycle proteins via the APC/C complex. While annotating the Eukaryotic Linear Motif resource (ELM, http://elm.eu.org/), we found that KEN motifs were significantly enriched in human protein entries with cell cycle keywords in the UniProt/Swiss-Prot database—implying that KEN-boxes might be more common than reported. Results: Matches to short linear motifs in protein database searches are not, per se, significant. KEN-box enrichment with cell cycle Gene Ontology terms suggests that collectively these motifs are functional but does not prove that any given instance is so. Candidates were surveyed for native disorder prediction using GlobPlot and IUPred and for motif conservation in homologues. Among >25 strong new candidates, the most notable are human HIPK2, CHFR, CDC27, Dab2, Upf2, kinesin Eg5, DNA Topoisomerase 1 and yeast Cdc5 and Swi5. A similar number of weaker candidates were present. These proteins have yet to be tested for APC/C targeted destruction, providing potential new avenues of research. Contact: toby.gibson@embl.de Supplementary information: Tables of KEN-box candidates and keyword/conservation significance assessments are available as supplementary data at Bioinformatics online. [ABSTRACT FROM AUTHOR]