Short introduction Epigenetic Regulation of Gene Expression

Group leader: Prof. dr. A.P. (Arie) Otte

In all eukaryotes higher order gene control mechanisms exist that activate or repress parts of the genome via changes in chromatin structure. These higher order gene control systems form an important molecular basis of cell differentiation. Our research group tries to understand molecular mechanisms underlying epigenetic regulation of gene expression. In the past, research has been focused on unraveling the function of the gene repressing Polycomb group (PcG) protein complexes. These PcG complexes are part of a cellular memory system that is responsible for the inheritance of gene activity to progeny cells. In the genome, the action of PcG complexes is delimited by so-called STAR elements, genomic DNA elements that counteract PcG mediated gene repression.

We found that STAR elements that block epigenetic gene repression can be utilized to augment the expression of exogenous genes that have been stably incorporated in the genome of a host cell. This property can, for instance, be used to enhance the production of therapeutic proteins in mammalian cells. Often these are very difficult to produce, which in turn leads to very high costs of these therapeutic agents. Application of STAR elements, in combination with very stringent selection systems that we developed, has been recognized as being of great biotechnological value.

Based on the results with the STAR technology, we recently developed novel means to select stably transfected mammalian cell lines. We further discovered novel genetic elements with the ability to enhance recombinant gene expression in mammalian cell lines. Although these elements are structurally different, they have in common that they are themselves sources of active transcription that interfere positively with other promoters. These lines of research have an important medical biotechnological component.