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2008: First annual symposium of the Luxembourg Bioinformatics Network (LuciLinX)

The symposium took place on October 16th 2008 at the “Chambre de Commerce” conference centre. It was organised by the CRP-Santé, in cooperation with LuxInnovation, the National Agency for Innovation and Research, in the context of their Health Sciences and Technologies Cluster project “BioHealth”. Funding was kindly provided by CRP-Santé and the University of Luxembourg.

Abstracts

Bioinformatics for microarray analysis

MULLER Arnaud, NAZAROV Petr, NICOT Nathalie, BERNARDIN François and VALLAR Laurent. Microarray Center / CRP-Sante, 84 Val Fleuri, L-1526.

The CRP-Santé Microarray Center provides scientists with centralized resources necessary to conduct functional genomics studies. The Center collaborates with several laboratories from Luxembourg and foreign institutions on research projects in areas as diverse as health, food tracing and environmental issues. Gene expression analyses are carried out at the Center using a wide spectrum of commercial and in-house, custom-designed microarrays, generating large amounts of data with heterogeneous features. Processing, mining and storage of these data are challenging and require robust biostatistics and bioinformatics procedures based on high performance and flexible software. To guarantee the quality and comparability of microarray data, analyses should be performed according to highly standardized procedures that comply with international guidelines (MIAME, MAQC).

We will present the different methodologies and tools that we established or developed for managing the key steps in a microarray analysis, including microarray probe design, image processing, statistical preprocessing (quality assessment), statistical analysis, data mining and data storage.

New tools for metadata extraction and image analysis for SIMS and confocal microscopy: applications in biology using isotopically labelled probes

Patrick Pirrotte 1, Jérôme Mutterer 2, Jean-Nicolas Audinot 3, Claude P. Muller 1 1 Institute of Immunology (CRP-Santé / Laboratoire National de Santé) 2 Institut de Biologie Moléculaire des Plantes de Strasbourg (CNRS) 3 Science and Analysis of Materials (CRP- Gabriel Lippmann)

In life sciences, conventional microscopy mainly relies on fluorescent molecular probes to specifically target sites of interest, with expected resolution and sensitivity linked to their size and mechanism of action. However, these techniques present several drawbacks, such as fluorophore cytotoxicity or shadowing effects induced by steric hindrance of labelled biomarkers. Secondary ion mass spectrometry (SIMS) allows for the direct imaging of ions, reducing the need of probes or, in some cases, obviating them altogether. The NanoSIMS is a dynamic SIMS ion microprobe capable of imaging the distribution of elemental ions at high lateral resolution, mass resolution and sensitivity. We are currently exploring its capabilities for image-based microanalysis of biological samples, in conjunction with small-sized halogen based probes and isotopically labelled biomolecules. The lack of free imaging software able to fully read the CAMECA image format and to extract analytical parameters from the data files compelled us to develop utilities based on the ImageIO and ImageJ frameworks. These include metadata extraction and semi-automated image processing and implement several algorithms for ratiometric data analysis and particle identification. Their use is illustrated in the studies of antigen uptake and protein localization using SIMS specific immunolabelling. To confirm our results, SIMS data were complemented by confocal microscopy for which similar image processing tools were developed.

Transcriptome analysis of the molecular effects of Heteronemin, a sesterterpene from the marine sponge Hyrtios reticulata, on K562 human leukemia cells

Serge Eifes 1, Marc Schumacher 1, Sébastien Chateauvieux 1, Mario Dicato 1, Marcel Jaspers 2 and Marc Diederich 1 1 Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg 2 Department of Chemistry, University of Aberdeen, Old Aberdeen, AB24 3UE, U.K.

Marine ecosystems represent an interesting source for pharmacologically active compounds including Heteronemin. This scalarene sesterpene from Dictyoceratida sponges shows cytotoxic anti-cancer properties. Results from whole genome microarray experiments were analyzed for statistical over-representation of gene annotations including Transcription factor binding motifs, Gene Ontology Biological Processes and Molecular Functions. Impacted transcriptional networks and molecular processes are discussed.

Computer-based approaches for the analysis of biosystems in vitro and in living cells.

YATSKOU, Mikalai, LE BECHEC, Antony, and Evelyne FRIEDERICH Cytoskeleton and Cell Plasticity Laboratory, Life Sciences Research Unit, Faculty of Sciences, Technology and Communication, Campus Limpertsberg, University of Luxembourg, 162A, avenue de la Faïencerie, L-1511.

The team aims at studying the function of the Actinome (expressed cytoskeleton genes) at different levels of systems complexity to understand how the actin cytoskeleton contributes to cell plasticity (morphogenesis, differentiation/dedifferentiation, migration), with a specific focus on cancer. Combining cell-based assays with transcriptomic analysis (including miRNAs) we also study molecular circuits involved in epithelial cancer cell invasion a key step of cancer progression to a metastatic, life-threatening state. Relevant skills and competences of the team in mathematics, biostatistics and bio-computing will be presented: 1) stochastic Monte Carlo simulation methodology which is a cornerstone for implementing analytic and predictive models with a broad application in many areas, including industry. 2) standardised biostatistical methodologies for high-throughput microarray data, based on the use of fluorescent probes (e.g. optimized analysis pipeline for the extraction of biological information from microarray data). Illustrations of current developments in stochastic modeling of the dynamics of biochemical reactions in vitro and in living cells will be given (e.g. ActinSimChem, http://sysbiocell.uni.lu/actinsim ; FRAPanalyser). Future development in bioinformatics aiming at unraveling microRNA circuits in cancer cell invasion will be discussed (FNR project BIOSAN 07/12). Back to top

Omics resource for transcription factors and subsequent applications

Merja Heinäniemi, Life Sciences Research Unit, Faculty of Sciences, Technology and Communication, Campus Limpertsberg, University of Luxembourg, 162A, avenue de la Faïencerie, L-1511.

Our aim is to efficiently integrate the genomics and transcriptomics datasets collected in the group for follow-up analysis, such as finding regulatory SNPs as presented here.

Bioinformatic activities at the department ‘Environment and Agro-Biotechnologies’ at CRP-Gabriel Lippmann

Danièle Evers, evers@lippmann.lu

The sustainable management of natural resources requires a major scientific and technological effort that can only be achieved through a multidisciplinary scientific approach. EVA has thus developed a multidisciplinary expertise in the environment and agro-biotechnologies, following four lines of development and innovation:

earth sciences and land-use management
sciences of the natural and anthropic environment, and their eco-technology applications
life sciences (animal and plant biology) and their bio-technology applications in agriculture, forestry, horticulture and viticulture
nutrition and toxicology

Bioinformatic tools are used at several levels. An overview will be given of the projects and available infrastructure implementing these tools. They include e.g. studies of plant-stress interactions, where systems biology is used to unravel the very complex responses. In this context, transcriptomis, proteomics and metabolomics technologies are applied to identify differentially expressed genes and proteins as well as implicated metabolites, respectively. Other projects are in the domain of phylogenomics using full genome comparative approaches to answer questions relevant to pathogenicity and evolution of particular traits of fungi such as toxins. Imaging tools are used among others to visualize the distribution of toxicants at the cellular level in view of the mechanistic understanding of their activity. State-of- the art equipment in genomics, proteomics, metabolomics, microscopy (inc. SIMS), and high-performance computing are available to generate, manage and exploit the necessary data.

From gene comparison to genome comparison: new opportunities and perspectives for microorganisms

Matias Pasquali, pasquali@lippmann.lu

The availability of an increasing number of genomes in the microbial world and the efficiency of bioinformatics tools are transforming taxonomical research as well as opening new research perspectives for addressing questions related to the evolution of microorganisms.

An overview of the applications used for genome analysis at the CRP-Gabriel Lippmann is presented for microorganisms that are of interest from an environmental or food safety perspective.

Moreover, one example of genome comparison among micro-fungi is described to demonstrate the potentiality of genome comparison for understanding regulation of relevant genetic traits such as mycotoxin production.

Tools for the identification of proteins from non-model species: a case study on oak

Kjell Sergeant, sergeant@lippmann.lu

Most of the scientific discoveries in the field of proteomics, and certainly those that attract attention outside scientific literature are achieved by using a small group of well-defined organisms. The importance of these so called model-organisms (E. coli, mouse, yeast, arabidopsis, rat, Homo sapiens, …) as a tool in data-driven research can not be neglected. However, even the full description of these organisms, a goal far from attained, is very unlikely to uncover all phenomena of life. Because of this the study of other than model-organisms will remain important.

All model organisms are completely sequenced at the genome level and extensive protein and mRNA databases are available for these organisms, as such protein identification in projects using these organisms has become routine. However, the high-throughput large-scale approaches that were developed for the identification of proteins from model-organisms are less than optimized if sequence information is lacking.

In this presentation some of the tools that are used at the CRP-GL for the identification of proteins for which no sequence is present in databases is illustrated in a case study on oak.

The Information Technology Side of the Integrated BioBank of Luxembourg

Nico Mack, Centre de Recherche Public Henri Tudor, CR SANTEC

Partnering with Tgen, Luxembourg will develop the Integrated BioBank of Luxembourg (IBBL), a biorepository and production core that will serve Luxembourg and its partners to collect, store and redistribute biospecimens and their related clinical data; and to produce analytes suitable for analyses by state-of-the-art genomics and proteomics platforms.

The SANTEC department of the CRP Henri Tudor gives a brief overview of the IT architecture and the timeline for the development and the deployment of the IBBL. The presentation gives an outline of the role SANTEC has in the whole project and how Luxembourg can put it to best use.

Wikipathways, using community knowledge to understand genomics

Chris Evelo. Department of Bioinformatics – BiGCaT. Maastricht University.

Background. Maintaining digital representations of biological pathways has several advantages. For example, pathway representations can act as carriers of scientific knowledge and help analysis and interpretation. The value of biological pathways is greatest when they are frequently updated and shared between researchers. Collecting new information resulting from biological research around the world is a major challenge. An online community has a greater capacity for dealing with such a large information load than a private group of curators. Good software is needed to make this process possible, as well as painless and efficient.

The resource. We developed WikiPathways, a website for collaborative pathway editing and sharing. WikiPathways is a public space where pathways are contributed and maintained by the users. By following this wiki concept, we hope to provide a more up-to-date and dynamic representation of the current biological knowledge than existing pathway databases. Features of WikiPathways are:

Collaborative editing, multiple users can work on the same pathway, review and discuss their modifications
A version history is saved, so all modifications can be reverted. Modifications can easily be reviewed using a visualization of the differences between two versions.
Links to literature and annotations in other biological databases can be added to a pathway, to improve integration with the available biological resources.
Graphical storage of pathway layout through GPML, or GenMAPP Pathway Markup Language. GPML is designed to bridge the gap between the BioPAX standard and the GenMAPP format, which stores coordinates and graphical annotations. This format supports node-edge relationships, making it compatible with biological network analysis tools such as Cytoscape.
Pathways can be exported to several other formats, such as GenMAPP for data mapping and SVG or PDF for publication.

Understanding genomics. While the visual presentation of pathways alone can already be very helpful to understand complex biological problems the real benefit of the pathways on WikiPathways is that they can immediately be used for analysis. Pathways can be exported to the old GenMAPP format for usage in the well known pathway analysis combo GenMAPP/ MappFinder. They can also be used in pathway statistics tool Eu.Gene and lists of genes and metabolites can be exported for further statistical analysis. Our new pathway analysis tool, developed in collaboration with Bruce Conklin’s GenMAPP group, allows more advanced data representations for both gene and metabolite related omics results. A Cytoscape plugin allows cut and paste communication between pathways in WikiPathways and PathVisio and Cytoscape, and thus enables all aspects of network analysis in Cytoscape.

WikiPathways and PathVisio are both open source software projects, freely available from http://www.wikipathways.org and http://www.pathvisio.org.

WikiPathways: Pathway Editing for the People. Pico AR, Kelder T, van Iersel MP, Hanspers K, Conklin BR and Evelo CTA (2008). PLoS Biol 6(7): e184.
Presenting and exploring biological pathways with PathVisio. Martijn P van Iersel, Thomas Kelder, Alexander R Pico, Kristina Hanspers, Susan Coort, Bruce R Conklin, Chris Evelo (2008). BMC Bioinformatics (in press).
Big data: Wikiomics. Mitch Waldrop. Nature 455, 22-25 (2008).
We the curators. Allison Doerr. Nature Methods 5, 754 - 755 (2008).

Modeling and Inference of Transcriptional Regulatory Networks

Ilya Shmulevich, Institute of Systems Biology ISB, Seattle, USA

Living systems are manifestations of their underlying complex dynamical networks of molecular interactions. A paramount problem is to understand how functional cellular behavior and interaction with the cell's environment is mediated by these complex molecular systems. Recent advances in measurement technologies allow us to interrogate biological systems and collect massive amounts of heterogeneous information under a variety of experimental conditions. Integrating this information and constructing predictive models of system behavior are the central goals of systems biology. I will discuss our efforts focused on the inference of models of transcriptional regulatory networks from high-throughput measurement data, integration of multiple sources of evidence, network simulation and visualization tools, and the use of such models for gaining insight into the nature of cellular behavior in health and disease.