Abstract
The three-dimensional architecture of chromosomes, their arrangement, and dynamics within cell nuclei are still subject of debate. Obviously, the function of genomes—the storage, replication, and transcription of genetic information—has closely coevolved with this architecture and its dynamics, and hence are closely connected. In this work a scale-bridging framework investigates how of the 30 nm chromatin fibre organizes into chromosomes including their arrangement and morphology in the simulation of whole nuclei. Therefore, mainly two different topologies were simulated with corresponding parameter variations and comparing them to experiments: The Multi-Loop-Subcompartment (MLS) model, in which (stable) small loops form (stable) rosettes, connected by chromatin linkers, and the Random-Walk/Giant-Loop (RW/GL) model, in which large loops are attached to a flexible non-protein backbone, were simulated for various loop and linker sizes. The 30 nm chromatin fibre was modelled as a polymer chain with stretching, bending and excluded volume interactions. A spherical boundary potential simulated the confinement to nuclei with different radii. Simulated annealing and Brownian Dynamics methods were applied in a four-step decondensation procedure to generate from metaphase decondensated interphase configurations at thermodynamical equilibrium. Both the MLS and the RW/GL models form chromosome territories, with different morphologies: The MLS rosettes result in distinct subchromosomal domains visible in electron and confocal laser scanning microscopic images. In contrast, the big RW/GL loops lead to a mostly homogeneous chromatin distribution. Even small changes of the model parameters induced significant rearrangements of the chromatin morphology. The low overlap of chromosomes, arms, and subchromosomal domains observed in experiments agrees only with the MLS model. The chromatin density distribution in CLSM image stacks reveals a bimodal behaviour in agreement with recent experiments. Combination of these results with a variety of (spatial distance) measurements favour an MLS like model with loops and linkers of 63 to 126 kbp. The predicted large spaces between the chromatin fibres allow typically sized biological molecules to reach nearly every location in the nucleus by moderately obstructed diffusion and is in disagreement with the much simplified assumption that defined channels between territories for molecular transport as in the Interchromosomal Domain (ICD) hypothesis exist and are necessary for transport. All this is also in agreement with recent selective high-resolution chromosome interaction capture (T2C) experiments, the scaling behaviour of the DNA sequence, the dynamics of the chromatin fibre, the diffusion of molecules, and other measurements. Also all other chromosome topologies can in principle be excluded. In summary, polymer simulations of whole nuclei compared to experimental data not only clearly favour only a stable loop aggregate/rosette like genome architecture whose local topology is tightly connected to the global morphology and dynamics of the cell nucleus and hence can be used for understanding genome organization also in respect to diagnosis and treatment. This is in agreement with and also leads to a general novel framework of genome emergence, function, and evolution.
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Acknowledgements
J. Langowski needs to be thanked for the many discussions, the many a suggestion, and supporting parts of this work. J. Langowski, K. Rippe, M. Wachsmuth, W. Waldeck, and A. Bachmann are thanked for critical reading of the manuscript. The following people need to be thanked who supported and influenced this work of T.A.K especially T. Weidemann, K. Fejes-Toth, M. Göker, R. Lohner, M. Stör, E. Spiess, K. Rippe, W. Waldeck, C. Cremer, T. Cremer, K. Erenpreisa, A. Ollins, D. Ollins, C. C. Murre, J. Skok, F. G. Grosveld, and K. Egger. This work was supported mainly by the Bundesministerium für Bildung und Forschung (BMBF) under grant # 01 KW 9602/2 (Heidelberg 3D Human Genome Study Group, German Human Genome Project). T. A. Knoch was kindly provided with a dissertation grant of the German Cancer Research Center (DKFZ) during which the main part of this work was done. The EpiGenSys virtual consortium lab is also thanked for its input at a later stage of this work. In this respect this work was also supported by ERASysBio+/FP7 and the nationals funding organizations (the Dutch Ministry for Science and Education, the Netherlands Science Organization, the UK Biotechnology and Biological Sciences Research Council, and the Bundesministerium für Bildung und Forschung (BMBF)). The High-Performance Computing Center Stuttgart (HLRS; grant HumNuc), the Supercomputing Center Karlsruhe (SCC; grant ChromDyn), and the Computing Facility of the German Cancer Research Center (DKFZ) are thanked for access to their CRAY T3E and IBM SP2s in the initial part of this work as well as the BMBF under grant #01AK803A (German MediGRID), and #01IG07015G (Services@MediGRID). Special thanks also go to all those institutions, universities, and companies providing us with ~500.000 CPUh per day via computational grid resources: the German D-Grid, the European Grid Initiative EGEE, as well as the Erasmus Computing Grid the Almere Grid, and all the unnamed computing grids there is access through via these. Very specially thanks go also to all the world-wide distributed and unnamed donors of desktop computer power of our world-wide Correlizer@home BOINC grid!
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Knoch, T.A. (2022). Simulation of Different Three-Dimensional Models of Whole Interphase Nuclei Compared to Experiments - A Consistent Scale-Bridging Simulation Framework for Genome Organization. In: Kloc, M., Kubiak, J.Z. (eds) Nuclear, Chromosomal, and Genomic Architecture in Biology and Medicine. Results and Problems in Cell Differentiation, vol 70. Springer, Cham. https://doi.org/10.1007/978-3-031-06573-6_18
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