The synthesis of proteins, maintenance of structure and duplication of the eukaryotic cell itself are all fine-tuned
biochemical processes that depend on the precise structural arrangement of the cellular components. The
regulation of genes – their transcription and replication - has been shown to be connected closely to the threedimensional
organization of the genome in the cell nucleus. Despite the successful linear sequencing of the
human genome its three-dimensional structure is widely unknown.
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 100kbp 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). We also 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. Craig 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).
Best agreement between simulations and experiments is reached for a Multi-Loop-Subcompartment model with
a loop size of 126 kbp which are forming rosetts and are linked by a chromatin linker of 126 kbp. We also
hypothesize a different folding structure for maternal versus paternal chromosome 15. In simulations of whole
cell nuclei this modell also leads to distinct chromosome territories and subcompartments. A fractal analysis of
the simulations leads to multifractal behavior in good agreement with predictions drawn from porous network
research
