Conte, Mattia (2021) Polymer physics models to unveil the mechanisms of chromosome 3D organization at the single-molecule level. [Tesi di dottorato]

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Abstract

Human chromosomes have a complex 3D structure as genes and their regulators located far along the chain have to physically interact. Such an architecture is crucial to define the fate of a cell by establishing active and silenced genes. However, the molecular and physical principles underlying chromosome folding remain poorly understood. We developed models of polymer physics of chromosomes to understand the mechanisms whereby distal DNA sequences recognize and interact with each other to shape the folding of our genome and its functions. By crossing physics models, computer simulations and genomic datasets, we provided evidence that chromosome architecture is controlled by mechanisms of thermodynamics phase transitions. Those theories have been confirmed by recent experiments (such as Hi-C, GAM, SPRITE, and super-resolution microscopy), in particular, on their predictions on how genome physical interactions, e.g., between genes and their regulators, are established at the single-molecule level (see, e.g., Nature Communications, 11, 3289 (2020), Nature Methods, 18, 482 (2021), Nature Structural & Molecular Biology, 28, 152–161 (2021) and Nature Genetics, 53, 1064–1074 (2021)).

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