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

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Our genetic information is stored in the base sequence encoded by our DNA, and the DNA molecules that run the length of each human chromosome are arguably the longest and most important biomolecules known. But although we now know their DNA sequences, we still know almost nothing about how that DNA is folded in 3-D space within the nucleus of a living cell. Common sense suggests there must be some underlying order within the apparent tangle. As a result, the relation of the 3-D dynamic architecture with function - the storage and expression of genetic information - remains one of the central unresolved issues of our time. It has become clear that genomes are tremendous coevolutionary and interwoven molecular storage machines able to manipulate and fabricate information: the genetic information is coded in and along these long molecules, and these molecules are continually being modified spatially and temporally through a multi-dimensional interaction and regulatory network. Therefore, a full understanding of structure-function relationships requires knowledge not only of the linear base-pair composition, but also of its structural and dynamic organization. The human genome encodes information on several levels: i) the famous DNA double helix, ii) which winds around a protein complex (the nucleosome), iii) and condenses into a higher-order 'chromatin' fiber, iv) that is folded into loops, v) which aggregate in turn into chromosomal subdomains, vi) that form 'territories', vii) which are arranged in a complex way in the nucleus. Modifications acting as a code and affecting function are found at all these levels. Therefore, in 'EpiGenSys' we have established an unique consortium of European scientists with the aim of achieving a major breakthrough in the determination and understanding of the relation between DNA sequence, the 3-D folding, and the way the system is able to access and read ('transcribe') the information. Using a truly inter-disciplinary approach, we plan to integrate the following set of projects: i) The investigation of the dynamic structure locally at the level of the nucleosome and globally at the level of the fiber. ii) The determination of intra/inter chromosomal interactions and the organization of territories. iii) The analysis of the genetic readouts - the transcriptional states - and their relation to the underlying structure. iv) The simulation (using super-computers) of the structure at the level of nucleosomes, fibers, and whole chromosomes to provide theoretical insight. v) The integration of i) to iv) into a mathematical model of the whole system that will be accessed using a special web browser that will facilitate the viewing (and manipulation) of all the different kinds of data. We expect through reiterative cycling between experiment and theory that we will be able to address a central issue of the genomic era - the way structure influences gene activity (and vice versa). Projects i) through iii) involve (wet) experimental science (cell and molecular biology), while projects iv) and v) utilize computers and mathematical modelling (and so involve mathematicians, physicists, and bioinformaticians) . PR Cook will be involved in projects ii), iii) and iv), and so will work on both sides of the cultural divide.