Annunziatella, Carlo (2018) Investigating the three-dimensional architecture of genomes by polymer physics. [Tesi di dottorato]

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In mammalian cell nuclei, chromatin has a spatial organization that is strictly related to cellular biological functions, such as regulation of gene transcription and expression. However, still today, chromatin structure is currently poorly understood despite being subjected to intense investigation. Recent findings have revealed that chromatin has a complex, hierarchical organization spanning from the sub-Mb scale up to the entire chromosome length. To shed light on this intricate pattern of interactions revealed by experimental data, polymer physics models have been introduced. In this work, we focused on the “String&Binders Switch” (SBS) model, where non-random chromatin conformations are established through specific interaction of chromatin with diffusing DNA-binding molecules, driving folding by formation of loops. The SBS model recapitulates several features of chromatin organization, such as the large-scale average behavior of experimental data, the mechanisms underlying the self-assembly of TADs and the hierarchical organization of genome, as emerging from experimental data. Moreover, by the SBS model, it is possible to reconstruct the 3D architecture of real genomic regions with high accuracy, without any a-priori knowledge of the molecular factors responsible for chromatin folding. Importantly, our polymer models are able to predict the effects of structural variants in the genomic sequence on the 3D architecture, with a very good accuracy. In this scenario, our polymer modeling methods emerge as a powerful approach to predict pathogenic effects, facilitating the interpretation and diagnosis of this type of genomic rearrangements.

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