Project: System Biological Determination of the Epigenomic Structure-Function Relation

Despite our knowledge of the sequence of the human genome, the relation of its dynamic three-dimensional architecture with its function ? the storage and expression of genetic information ? remains one of the central unresolved issues in biology. However, it became very clear meanwhile, that this chromatin architecture (and changes thereof) are central factors for the epigenetic regulation of gene expression and other important genomic processes on multiple scales comprising: i) the nucleosome, in which 147 DNA base pairs are wrapped around a histone octamer protein core, ii) folding of the nucleosome chain into the chromatin fiber, iii) its higher-order organization into loops and iv) loop aggregates, as well as v) the chromosome. Despite recent advancements showing these levels to control holistically the function of genomes under normal and disease conditions we still remain unable to predict how active e.g. a gene might be when inserted into any one genomic location, i.e. another global context. Therefore, EpiGenSys will in a unique interdisciplinary systems biology virtual laboratory combine experiment with theory to analyze the (epi-)genomic structure-function relationships within the dynamic organization of several important genetic loci and the genome in general. We will investigate: i) the nucleosome and chromatin fiber organization, ii) 3D architecture of the genome, and iii) the transcription structure-function relationship. Therefore, we will use advanced high-throughput methods and highest-resolution microscopy. With extreme parallel super-computer simulations of the biological structures/architectures based on the experiments we will be able evaluate and predict their outcome. Altogether the experimental and theoretic framework will be combined in a systems biology model using our GLOBE 3D EpiGenSys Platform ? a completely novel virtual ?paper tool? for the analysis, manipulation and understanding of complex genome-wide data set. Consequently, the relation between DNA sequence, epigenetic modifications and spatial chromatin organization will be integrated with functional cell states in a truly systems biology approach ? an essential requirement to fullfil the dreams for better diagnostics and treatment e.g. by gene therapy in the 21st century.

Acronym EpiGenSys
Project Results
(after finalisation)
In EpiGenSys we have established a unique consortium with the aim of achieving a major breakthrough in the determination and understanding of the relation between DNA sequence, epigenetic modifications and spatial chromatin organization. Already in setting up the consortium we focused on: i) the interdisciplinary work experiences, ii) the scientific excellence, iii) the proven management capabilities both of the group and their institutions, and v) the complementary expertise and balance concerning dissemination and valorization. We believe this has generated a ’virtual laboratory’ necessary to address the biology of complex systems and by that address one of the major problems of our time, which would not have been possible otherwise. Transnational consortium structure: Here two major aspects were considered: i) social/management expertise and ii) scientific excellence with respect to our goals. Consequently, all team members in our ‘virtual laboratory’ have renowned track records covering decades of interdisciplinary research and their scientific excellence is reflected by their curriculum vitae and research profiles that have resulted in a huge number of patents, publications, talks and business activities which have gained them many prizes and awards. In terms of scientific excellence, all partners are well known and leading figures in the field of genome organization and function, with track records over 15 to 30 years. Unusually, they have all made important contributions to the systems biology of the field and are familiar to discussing problems with scientists in other disciplines, they know the vocabulary used in those and other disciplines, and have combined experiment with theory in their own research. Thus, they have not only applied systems approaches in the past, but they were excited about combining experiment with theory in the EpiGenSys virtual laboratory. The project partners and their work groups were integrated by a systems approach into EpiGenSys by two means as can be seen from the structure of the work packages. Since the expertise of the partners (each with their own established network of contacts) is outstanding, the work packages were set up in such a way that each would utilize established skills of individual partners while providing maximum benefit to the groups. Consequently, all work packages involved a minimum of 3 of the 5 partners (in different combinations). This working structure inevitably maximized both output and close cooperation, so knowledge has been generated and exchanged most efficiently. We believe that EpiGenSys successfully integrated participants, and generated close ties and further cooperation long beyond the initial funding period. In respect of the systems biology: EpiGenSys provided huge added value driven by its international nature coupled in the determination and understanding of the relation between DNA sequence, epigenetic modifications and spatial chromatin organization. The existing knowledge networks, resources and related projects of individual partners will synergized in a unique way. Additionally, the exchange of the work force and working cultures will enhance and develop the genomic community within Europe. Thus, the result of building a systems biological model of the genomic structure function relationship was not only achieved but also could not have been achieved otherwise. The publications and presentations as well as the further exploitation fulfil the ambitious goals of the project as can be seen from the list of publications and further studies in the making and make the success of EpiGenSys explicit!
Network ERASysBio+
Call ERASysBio+-2008-01

Project partner

Number Name Role Country
1 Erasmus Medical Center Coordinator Netherlands
2 University of Oxford Partner United Kingdom
3 German Cancer Research Center Partner Germany
4 University of Regensburg Partner Germany
5 University of Applied Sciences Stralsund Partner Germany