PD Dr. Karsten Rippe

Computer simulations of the dynamic structure of a nucleosome. The nucleosome consists of an octamer histone protein complex with DNA wrapped around it in almost two turns. It represents the basic building block of chromatin. In a human cell about 30 million nucleosomes organize the genome of 6 billion DNA base pairs. In the image nucleosome conformations are overlayed in 0.2 nanosecond time intervals. The DNA is color coded with increasing simulation time from red to white to blue. The core histone proteins are shown in white. Already during the very short simulation time period of 2 nanoseconds the nucleosome conformation is very dynamic. For further details of investigating nucleosome and chromatin features in computer simulations see Ettig et al. 2011, Biophys. J. and Kepper et al. 2008, Biophys. J.

The Genome Organization & Function group at the the DKFZ and the BioQuant is an interdisciplinary research team that combines molecular/cell biology and physics. It investigates the relation of the dynamic organization of the genome in the eukaryotic cell nucleus with the readout, processing, maintenance and transfer of the information encoded in the DNA sequence. A special focus is put on the conformation and dynamic properties of chromatin - the complex of the DNA genome with histones and other chromosomal proteins. Both the DNA and the protein component of chromatin are subject to post-translational modifications that include DNA/histone methylation, as well as acetylation and phosphorylation of histones. These epigenetic signals determine the cell's gene expression pattern and can be propagated through cell division. They are tightly related to chromatin organization, which in turn is a key determinant of access to DNA sequence information for interacting protein factors. The goal of the group is to provide an integrated view on how the dynamic balance between different chromatin states determines genome functions.

Understanding how chromatin states are established and maintained becomes increasingly important for medical diagnosis and therapy of cancer, developmental diseases and other pathologies. We will further advance the single cell analysis of epigenetic networks by fluorescence spectroscopy/microscopy-based techniques in living cells and integrate it with genome wide studies of nucleosome positioning, protein binding and histone modifications in cell populations based on DNA sequencing. The experimental results will serve as the basis for various modeling-based projects with respect to developing quantitative descriptions for the dynamic chromatin organization in the context of the dynamic nuclear architecture into subcompartments. The results from these studies are integrated to dissect the underlying networks. Our work has a number of implications for translational medical research with respect to elucidating the complex effects of epigenetic drugs like histone deacetylase or DNA methylase inhibitors in treatment of cancer. Accordingly, we plan to apply a number of approaches currently used with immortalized human and mouse cell lines to studies of primary cancer cells.

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