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• W2129969102 abstract "markdownabstractThe synthesis of proteins, maintenance of structure and duplication of the eukaryotic cell itself are all fine-tunedbiochemical processes that depend on the precise structural arrangement of the cellular components. Theregulation of genes – their transcription and replication - has been shown to be connected closely to the threedimensionalorganization of the genome in the cell nucleus. Despite the successful linear sequencing of thehuman 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 proteinswithout much internal structure, except during cell division when chromosomes are condensed into separateentities. Only recently has it become apparent that chromosomes occupy distinct 'territories' also in theinterphase, i.e. between cell divisions. In an analogy of the Bauhaus principle that follows function webelieve that analyzing in which form DNA is organized in these territories will help us to understand genomicfunction. We use computer models - Monte Carlo and Brownian dynamics simulations - to develop plausibleproposals for the structure of the interphase genome and compare them to experimental data. In the workpresented here, we simulate interphase chromosomes for different folding morphologies of the chromatin fiberwhich is organized into loops of 100kbp to 3 Mbp that can be interconnected in various ways. The backbone ofthe fiber is described by a wormlike-chain polymer whose diameter and stiffness can be estimated fromindependent measurements. The implementation describes this polymer as a segmented chain with 3000 to20000 segments for chromosome 15 depending on the phase of the simulation. The modeling is performed on aparallel 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 hybridisationmethod (in collaboration with I. Solovai, J. Craig and T. Cremer, Munich, FRG) conserving the structure of thenucleus. As probes we use 10 kbp long lambda clones (Prof. B. Horsthemke, Essen, FRG) covering genomicmarker distances between 8 kbp and 250 kbp. The markers are detected with confocal and standing wavefieldlight microscopes (in collaboration with J.Rauch, J. Bradl, C. Cremer and E.Stelzer, both Heidelberg, FRG) andusing 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 witha loop size of 126 kbp which are forming rosetts and are linked by a chromatin linker of 126 kbp. We alsohypothesize a different folding structure for maternal versus paternal chromosome 15. In simulations of wholecell nuclei this modell also leads to distinct chromosome territories and subcompartments. A fractal analysis ofthe simulations leads to multifractal behavior in good agreement with predictions drawn from porous networkresearch." @default.
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• W2129969102 date "1998-07-02" @default.
• W2129969102 modified "2023-09-26" @default.
• W2129969102 title "Three-dimensional organization of chromosome territories in the human interphase nucleus" @default.
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