The 22 projects in this collaborative research centre are aiming to understand the molecular function of chromatin. The local chromatin structure is a critical determinant of gene activity. Nucleosome remodelling may render a promoter accessible to transcription factors that in turn may recruit macromolecular complexes containing or associated with enzymes. Remodelling enzymes use energy derived from ATP hydrolysis to directly change interactions between DNA and histones resulting in changes in nucleosome position, structure or composition.

Chromatin regulating enzymes can covalently modify DNA, histones or other chromatin-associated proteins. These activities include protein acteylation, methylation, SUMO- and ubiquitin-modification as well as DNA methylation. Chromatin regulating enzymes are of fundamental importance. The failure to differentiate into or maintain a particular chromatin landscape is the hallmark of many diseases. Therefore, chromatin-regulating enzymes are attractive therapeutic targets as they offer a means to reshape the chromatin landscape of a cell. With the research program of this CRC we aim to understand the role of chromatin changes in normal cellular differentiation and in the steps leading to malignancy. Precisely we would like to understand the role and the mechanisms of chromatin-regulating enzymes during the development from stem cells to differentiated cells. Furthermore, we would like to unravel the nature and the interactions of specific complexes regulating gene activity. For all of these events a few molecular components are known, but the underlying functional mechanisms need to be worked out.

Local chromatin modification cannot function in isolation, since many thousands of similarly modified chromatin sites are found at only hundreds or even less locations in nuclear space. Furthermore, genes may be activated by regulatory elements that are located up to 1 megabase away from the promoter. Proper interactions, coordinated regulation of multiple genes and protection from flanking chromatin with adverse gene activity have to be accomplished. Insulators contribute to organize these interactions and to functionally separate active from inactive chromatin regions. Both, local and global chromatin compaction has to be precisely controlled. All of these require a higher order genome organization, the molecular function of which is not yet understood. Therefore, it remains a challenge to determine how the genome works at this higher order level of organization.

Obviously, both types, local enzyme actions and long range interaction of chromatin occur simultaneously, are tightly interwoven and are often dependent on one another. By addressing these questions jointly within the proposals of this CRC, we will be able to tackle these problems holistically, rather than being limited to single facets.