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Dreidimensionale Organisation von Chromosomen-Domänen in Simulation und Experiment

Three-Dimensional Organization of Chromosome Territories in Simulation and Experiment

Knoch, Tobias, Dr.,
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Zusammenfassung:
Um Aussagen über die dreidimensionale Organisation von Chromosomen in der Interphase zu machen, wurden Monte-Carlo- und Brownsche-Dynamik-Simulationen von Chromosomenterritorien mit Hilfe eines Polymeransatzes durchgeführt. Daraus wurden Observable (verschiedene Abstandsverteilungen zwischen genomischen Markern, Aufenthaltswahrscheinlichkeit und Dichte) berechnet, die für die Vorhersage und Interpretation von Experimenten dienen. Damit können Modelle der chromosomalen Organisation, insbesondere das Random-Walk-Giant-Loop- (MLS) und das Multi-Loop-Subcompartment-Modell, unterschieden werden. Für die Bestimmung von Abstandsverteilungen zwischen genomischen Markern der Prader-Labhart-Willi/Angelmann (PLWS/A) Region wurden Experimente mit einem konfokalen Laser-Scanning-Mikroskop (CLSM) durchgeführt. Zellkerne von Fibroblasten wurden mit schonender Fluoreszenz-in-situ-Hybridisierung (FISH) präpariert. Über die Signal-Brightness, das Signalvolumen, die Intergrierte Fluoreszenz Intensität (IFI) und den Abstand homologer Chromosomen wurden ebenfalls Aussagen gemacht.Vergleiche zwischen Simulation und Experiment ergaben starke Hinweise für das MLS-Modell, sowie eine unterschiedliche Organisation zwischen mütterlichem und väterlichem Chromosom 15.Im Hinblick auf zukünftige komplexere Fragestellungen der Gesamtorganisation des Zellkerns stellte sich die Theorie der Fraktale für neue Analysemethoden als geeignet heraus. Die Ergebnisse der Simulationen zeigte dabei multifraktales Verhalten. Erstmals könnte damit die Fraktalität und Multifraktalität einer zellulären Organisationsstruktur gezeigt worden sein. Damit besteht nun die Möglichkeit aus der fraktalen Struktur Aussagen über Diffusionseigenschaften und andere Organisationsmerkmale im Zellkern zu treffen.
Abstract:
To draw conclusions about the three-dimensional organization of interphase chromosomes, Monte-Carlo and Brownian-Dynamic simulations of chromosomal territories were conducted, using a polymer model for the chromatin fiber. From the simulated configuration ensembles observables (various distance distributions between genomic markers, radial space distribution and density) were calculated and used for predictions and interpretation of experiments. It was possible to distinguish between different models of chromosomal organization, especially between the Random-Walk-Giant-Loop- (RWGL) and the Multi-Loop-Subcompartment-model.For the determination of distance distributions between genomic markers of the Prader-Labhart-Willi/Angelmann region (PLWS/A) experiments were made with a confocal Laser-Scanning-Microscope (CLSM). Cell nuclei of fibroblast cells were prepared with soft Fluorescent-in-situ-Hybridization (FISH). Conclusions can be drawn from the signal-brightness, signal-volume, Integrated Fluorescent Intensity (IFI) and the distance between homologous chromosomes.Comparisons between simulation and experiment lead to strong hints for the MLS-model, as well as different organization of maternal and paternal chromsome15.With respect to future aspects of more complex questions on the total organization of cell nuclei the theory of fractals proved very worthwhile for new methods of analysis. The results of the simulations thereby showed multi-fractal behaviour. Thus, for the first time the fractal and multi-fractal behaviour of a cellular-organization-structure was determined. Consequently possibilities exist to draw conclusions from the fractal structure for diffusion behaviour and other organizational patterns of the cell nucleus.

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Titel: Dreidimensionale Organisation von Chromosomen-Domänen in Simulation und Experiment
Autoren/Herausgeber: Tobias Aurelius Knoch
Ausgabe: 2., Aufl.

ISBN/EAN: 9783000106859

Seitenzahl: 120
Format: 29 x 20,5 cm
Produktform: Taschenbuch/Softcover
Gewicht: 250 g
Sprache: Deutsch

Dr. Tobias A. Knoch was born as son of Wolfgang F. Knoch and Waltraut Knoch née List on 19th May 1971, in Mannheim, Germany. After four years of primary school, he attended the Lieselotte-Gymnasium Mannheim from 1982 to 1991, receiving the Abitur as primus (1991). From 1991 to 1992, he served at the Central Army Group (CENTAG), Heidelberg. From 1992 to 1998 he studied physics, mathematics and biology at the Ruperto-Carola University, Heidelberg: After the Vordiplom in Physics (1994) and in Mathematics (1994), he received his Diploma in Physics with the thesis presented here in the group of Prof. Dr. Jörg Langowski, Biophysics of Macromolecules, German Cancer Research Center (DKFZ), Heidelberg. There he also conducted his dissertation “Approaching the Three-Dimensional Organization of the Human Genome” from 1998 to 2002. Since 2002, he build up the international interdisciplinary group Biophysical Genomics at the Erasmus Medical Center, Rotterdam, The Netherlands, and was a member of the Kirchhoff Institute for Physics in Heidelberg and is also a member of the BioQuant Center/DKFZ. Since 2007 he is Assistant Professor at the Erasmus Medical Center.His work resulted in several patents and publications. He is founder, head, coordinator, and reviewer of several international interdisciplinary cooperative networks and consortia. Honourably, he received: nine prizes for excellent achievements at the Lieselotte-Gymnasium, the scholarship from the Studienstiftung des Deutschen Volkes, Bonn, awards of the Molecular Graphics and Modelling Society, San Diego (1998), and of the German Cancer Research Center (DKFZ, 1999), as well as the Klaus Goerttler Prize of the German Society for Cytometry (DGfZ, 2002). Besides his interests in fine arts and travelling, he is co-founder of BioContact e.V., co-organizer of the Contact-2001, -2002 and -2003 life-science industry fairs, as well as a member of The American Association for the Advancement of Science (AAAS), the Foresight Institute, the Bund für Umwelt und Naturschutz Deutschland (BUND), the German Society for Human Ecology (DGH), and the Human Ecology group at the Ruperto-Carola University, Heidelberg.

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