The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Mechanodetection of hemodynamics forces in the developing endocardium of Danio rerio

Les forces mécaniques dirigeant la valvulogénèse sont mal connues. Chez le poisson zèbre, le flux induit l’expression du facteur de transcription klf2a de façon endothéliale spécifique afin d’initier ce processus. Nous nous sommes intéressés aux mécanismes moléculaires activés par le flux et aboutissant à la formation des valves cardiaques. En altérant et modifiant le pattern fluidique, nous avons observé le rôle des forces engendrées par le flux pour le contrôle de l’expression de klf2a ainsi que du nombre de cellules endocardiques. Nous avons ensuite regardé les divers mécanosenseurs pouvant intervenir lors de ce processus. Ainsi nous avons mis à jour la présence de cils dans l’endocarde et fait la relation entre les canaux membranaires TRPP2 et TRPV4, la présence de calcium intracellulaire dans les cellules endocardiques et la voie moléculaire PKC-PKD2-HDAC5, composants nécessaires à l’expression du gène klf2a en réponse au flux. Ces données nous permettent de suggérer le rôle de TRPP2, TRPV4 et la voie moléculaire récemment découverte, PKC-PKD2-HDAC5 dans la formation valvulaire dépendante de klf2a.Mechanical forces that dictate valve formation are not well understood. In zebrafish, blood flow induces expression of the transcription factor klf2a in a specific subset of endocardial cells that will go on to form functional valves. We aimed to identify the molecular mechanisms activating this flow-induced valve formation. By altering and modifying blood flow patterns, we observed that flow-mediated forces are necessary to control early klf2a expression and endocardial cell numbers. We then looked at different mechanosensors operating at early stages of valve development. Using in vivo labelling, we identified primary cilia in the endocardium and showed that the membrane channels TRPP2 and TRPV4 increase intracellular calcium which activates a PKC-PKD2-HDAC5 pathway necessary for klf2a expression in response to flow. Together these data suggest a role for TRPV4, TRPP2 and the recently described PKC-PKD2-HDAC5 signalling pathway in klf2a-mediated valvulogenesis

Mécanodétection des forces hémodynamiques lors du développement endocardique chez l'espèce Danio rerio

Mechanical forces that dictate valve formation are not well understood. In zebrafish, blood flow induces expression of the transcription factor klf2a in a specific subset of endocardial cells that will go on to form functional valves. We aimed to identify the molecular mechanisms activating this flow-induced valve formation. By altering and modifying blood flow patterns, we observed that flow-mediated forces are necessary to control early klf2a expression and endocardial cell numbers. We then looked at different mechanosensors operating at early stages of valve development. Using in vivo labelling, we identified primary cilia in the endocardium and showed that the membrane channels TRPP2 and TRPV4 increase intracellular calcium which activates a PKC-PKD2-HDAC5 pathway necessary for klf2a expression in response to flow. Together these data suggest a role for TRPV4, TRPP2 and the recently described PKC-PKD2-HDAC5 signalling pathway in klf2a-mediated valvulogenesis.Les forces mécaniques dirigeant la valvulogénèse sont mal connues. Chez le poisson zèbre, le flux induit l’expression du facteur de transcription klf2a de façon endothéliale spécifique afin d’initier ce processus. Nous nous sommes intéressés aux mécanismes moléculaires activés par le flux et aboutissant à la formation des valves cardiaques. En altérant et modifiant le pattern fluidique, nous avons observé le rôle des forces engendrées par le flux pour le contrôle de l’expression de klf2a ainsi que du nombre de cellules endocardiques. Nous avons ensuite regardé les divers mécanosenseurs pouvant intervenir lors de ce processus. Ainsi nous avons mis à jour la présence de cils dans l’endocarde et fait la relation entre les canaux membranaires TRPP2 et TRPV4, la présence de calcium intracellulaire dans les cellules endocardiques et la voie moléculaire PKC-PKD2-HDAC5, composants nécessaires à l’expression du gène klf2a en réponse au flux. Ces données nous permettent de suggérer le rôle de TRPP2, TRPV4 et la voie moléculaire récemment découverte, PKC-PKD2-HDAC5 dans la formation valvulaire dépendante de klf2a

Mechanodetection of hemodynamics forces in the developing endocardium of Danio rerio

Les forces mécaniques dirigeant la valvulogénèse sont mal connues. Chez le poisson zèbre, le flux induit l’expression du facteur de transcription klf2a de façon endothéliale spécifique afin d’initier ce processus. Nous nous sommes intéressés aux mécanismes moléculaires activés par le flux et aboutissant à la formation des valves cardiaques. En altérant et modifiant le pattern fluidique, nous avons observé le rôle des forces engendrées par le flux pour le contrôle de l’expression de klf2a ainsi que du nombre de cellules endocardiques. Nous avons ensuite regardé les divers mécanosenseurs pouvant intervenir lors de ce processus. Ainsi nous avons mis à jour la présence de cils dans l’endocarde et fait la relation entre les canaux membranaires TRPP2 et TRPV4, la présence de calcium intracellulaire dans les cellules endocardiques et la voie moléculaire PKC-PKD2-HDAC5, composants nécessaires à l’expression du gène klf2a en réponse au flux. Ces données nous permettent de suggérer le rôle de TRPP2, TRPV4 et la voie moléculaire récemment découverte, PKC-PKD2-HDAC5 dans la formation valvulaire dépendante de klf2a.Mechanical forces that dictate valve formation are not well understood. In zebrafish, blood flow induces expression of the transcription factor klf2a in a specific subset of endocardial cells that will go on to form functional valves. We aimed to identify the molecular mechanisms activating this flow-induced valve formation. By altering and modifying blood flow patterns, we observed that flow-mediated forces are necessary to control early klf2a expression and endocardial cell numbers. We then looked at different mechanosensors operating at early stages of valve development. Using in vivo labelling, we identified primary cilia in the endocardium and showed that the membrane channels TRPP2 and TRPV4 increase intracellular calcium which activates a PKC-PKD2-HDAC5 pathway necessary for klf2a expression in response to flow. Together these data suggest a role for TRPV4, TRPP2 and the recently described PKC-PKD2-HDAC5 signalling pathway in klf2a-mediated valvulogenesis

Oscillatory Flow Modulates Mechanosensitive klf2a Expression through trpv4 and trpp2 during Heart Valve Development

In vertebrates, heart pumping is required for cardiac morphogenesis and altering myocardial contractility leads to abnormal intracardiac flow forces and valve defects [1-3]. Among the different mechanical cues generated in the developing heart, oscillatory flow has been proposed to be an essential factor in instructing endocardial cell fate toward valvulogenesis and leads to the expression of klf2a [4], a known atheroprotective transcription factor [5]. To date, the mechanism by which flow forces are sensed by endocardial cells is not well understood. At the onset of valve formation, oscillatory flows alter the spectrum of the generated wall shear stress (WSS), a key mechanical input sensed by endothelial cells. Here, we establish that mechanosensitive channels are activated in response to oscillatory flow and directly affect valvulogenesis by modulating the endocardial cell response. By combining live imaging and mathematical modeling, we quantify the oscillatory content of the WSS during valve development and demonstrate it sets the endocardial cell response to flow. Furthermore, we show that an endocardial calcium response and the flow-responsive klf2a promoter are modulated by the oscillatory flow through Trpv4, a mechanosensitive ion channel specifically expressed in the endocardium during heart valve development. We made similar observations for Trpp2, a known Trpv4 partner, and show that both the absence of Trpv4 or Trpp2 leads to valve defects. This work identifies a major mechanotransduction pathway involved during valve formation in vertebrates

OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation

The suppression of the receptor for oncostatin M (OSMR) can prevent glioblastoma cell growth. Here, the authors demonstrate a role for OSMR in modulating glioma stem cell respiration and its impact on resistance to ionizing radiation

Inhibition of type I PRMTs reforms muscle stem cell identity enhancing their therapeutic capacity

In skeletal muscle, muscle stem cells (MuSC) are the main cells responsible for regeneration upon injury. In diseased skeletal muscle, it would be therapeutically advantageous to replace defective MuSCs, or rejuvenate them with drugs to enhance their self-renewal and ensure long-term regenerative potential. One limitation of the replacement approach has been the inability to efficiently expand MuSCs ex vivo, while maintaining their stemness and engraftment abilities. Herein, we show that inhibition of type I protein arginine methyltransferases (PRMTs) with MS023 increases the proliferative capacity of ex vivo cultured MuSCs. Single cell RNA sequencing (scRNAseq) of ex vivo cultured MuSCs revealed the emergence of subpopulations in MS023-treated cells which are defined by elevated Pax7 expression and markers of MuSC quiescence, both features of enhanced self-renewal. Furthermore, the scRNAseq identified MS023-specific subpopulations to be metabolically altered with upregulated glycolysis and oxidative phosphorylation (OxPhos). Transplantation of MuSCs treated with MS023 had a better ability to repopulate the MuSC niche and contributed efficiently to muscle regeneration following injury. Interestingly, the preclinical mouse model of Duchenne muscular dystrophy had increased grip strength with MS023 treatment. Our findings show that inhibition of type I PRMTs increased the proliferation capabilities of MuSCs with altered cellular metabolism, while maintaining their stem-like properties such as self-renewal and engraftment potential

Dyslipidemia in retinal metabolic disorders

The light-sensitive photoreceptors in the retina are extremely metabolically demanding and have the highest density of mitochondria of any cell in the body. Both physiological and pathological retinal vascular growth and regression are controlled by photoreceptor energy demands. It is critical to understand the energy demands of photoreceptors and fuel sources supplying them to understand neurovascular diseases. Retinas are very rich in lipids, which are continuously recycled as lipid-rich photoreceptor outer segments are shed and reformed and dietary intake of lipids modulates retinal lipid composition. Lipids (as well as glucose) are fuel substrates for photoreceptor mitochondria. Dyslipidemia contributes to the development and progression of retinal dysfunction in many eye diseases. Here, we review photoreceptor energy demands with a focus on lipid metabolism in retinal neurovascular disorders