In this program we choose to integrate theoretical & experimental physics expertise with biological know-how. Six experimental physics groups with complementary expertise will participate (see table). Moreover, three theoretical and four biological groups were chosen to cover each of the sub-topics as depicted in figure 2. The resulting cluster of research groups will work together on key biophysics questions regarding DNA organization. These questions and the distribution of the research tasks are summarized in six different work packages. work packages 1-3 are mostly related to Chromatin structure, work packages 4-5 mostly to DNA maintenance and number 6 to Gene expression. Different groups will take the lead in the different work packages but the elucidation of these problems relies on sharing experimental, theoretical, biochemical expertise.

This scientific program will be coordinated by a team of five members (N. Dekker, C. Dekker, B. Mulder & P. Verrijzer) chaired by the program leader (G.J.L. Wuite). Once a year all members and participants of the program will meet in a symposium or summer school.

The advent of rapid DNA sequencing has revolutionized life sciences, allowing genome-wide analysis of gene regulation. Furthermore, molecular, biochemical and cell biological studies have revealed that the packaging of eukaryotic genomes into chromatin constitutes a key regulatory step in the control of genome maintenance, replication and expression. This is exemplified by the implication of multiple chromatin remodelers and histone modifying enzymes in human diseases, such as mental retardation and cancer. These and related discoveries will revolutionize medicine within our lifetime. Physicists will play an important role in future developments in biology, because they are trained to quantitatively describe, logically underpin, and formally unify seemingly disparate phenomena. Description of the molecular machinery inside cells necessitates close collaborations between biologists and physicists. Our goal is to unravel the physical processes linking fundamental biological processes ranging from DNA maintenance to gene regulation. We propose to achieve this through observation of simplified reconstituted systems at the single molecule level in parallel to detailed measurements in vivo so as to develop descriptive models that comply with both types of experimental observations.

Detailed physical insight in these processes will be vital to the development of small molecule inhibitors that specifically target chromatin dynamics. This will impact the cure of human diseases ranging from mental retardation, cancer and age-related diseases. Indeed, topoisomerase inhibitors already form an important class of anti-cancer drugs. Therefore, it is expected that drugs targeting other modulators of genome organization have the potential to result in important therapeutics as well.