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EpiGenSys - 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.

Project partners:

Tobias A. Knoch, Project Coordinator
Erasmus University Rotterdam, NL

Peter R. Cook
University of Oxford, UK

Karsten Rippe
BioQuant Centre (DKFZ Heidelberg), DE

Gernot Längst
University of Regensburg, DE

Gero Wedemann
University of Applied Sciences Stralsund, DE

 From left to right: Knoch, Grosveld, Rippe, Längst, Wedemann, Cook