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Three-dimensional organization
of a self-replicating nano-fabrication site:
the human cell nucleus

Tobias A. Knoch*, Christian Muenkel and Joerg Langowski

Division Biophysics of Macromolecules, German Cancer Research Centre

This is an abstract for a poster to be presented at the
Fifth Foresight Conference on Molecular Nanotechnology.
There will be a link from here to the full article when it is available on the web.

 

The eukaryotic cell is a prime example of a functioning nano-machinery. The synthesis of proteins, maintenance of structure and duplication of the machinery itself are all fine-tuned biochemical processes that depend on the precise structural arrangement of the cellular components. Especially the regulation of genes has been shown to be connected closely to the organization of the genome in the nucleus.

The nucleus of the cell has for a long time been viewed as a 'spaghetti soup' of DNA bound to various proteins without much internal structure, except during cell division when chromosomes are condensed into separate entities. Only recently has it become apparent that chromosomes occupy distinct 'territories' also in the interphase, i.e. between cell divisions. In an analogy of the Bauhaus principle that "form follows function" we believe that analyzing in which form DNA is organized in these territories will help us to understand genomic function. We use computer models - Monte Carlo and Brownian dynamics simulations - to develop plausible proposals for the structure of the interphase genome and compare them to experimental data. In the work presented here, we simulate interphase chromosomes for different folding morphologies of the chromatin fiber which is organized into loops of 100 kbp to 3 Mbp that can be interconnected in various ways. The backbone of the fiber is described by a wormlike-chain polymer whose diameter and stiffness can be estimated from independent measurements. The implementation describes this polymer as a segmented chain with 3000 to 20000 segments for chromosome 15 depending on the phase of the simulation. The modeling is performed on a parallel computer (IBM SP2 with 80 nodes). Currently we determine genomic marker distributions within the Prader-Willi-Region on chromosome 15q11.2-13.3. For these measurements we use a fluorescence in situ hybridisation method (in collaboration with I. Solovai, J. Crai and T. Cremer, Munich, FRG) conserving the structure of the nucleus. As probes we use 10 kbp long lambda clones (Prof. B. Horsthemke, Essen, FRG) covering genomic marker distances between 8 kbp and 250 kbp. The markers are detected with confocal and standing wavefield light microscopes (in collaboration with J.Rauch, J. Bradl, C. Cremer and E.Stelzer, both Heidelberg, FRG) and using special image reconstruction methods developed solely for this purpose (developed by R. Eils. and W. Jaeger, Heidelberg, FRG).

The work is part of the Heidelberg 3D Human Genome Study Group, which is part of the German Human Genome Project.


*Corresponding Address:
Tobias A. Knoch, Division Biophysics of Macromolecules, German Cancer Research Centre, Im Neuenheimer Feld 280, D - 69120 Heidelberg, Germany, ph: +49-6221/423394 or 423392 fax: +49-6221/422291 email: TA.Knoch@DKFZ-Heidelberg.de



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