Vercellone, Francesca (2025) Polymer physics of single-cell chromatin architecture: structural and epigenetic variability. [Tesi di dottorato]

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Abstract

The three-dimensional (3D) genome organization plays a fundamental role in regulating gene expression and cellular identity. Advances in chromosome conformation capture technologies, such as Hi-C, have revealed the multiscale architecture of chromatin. However, population-averaged Hi-C data obscure the structural variability that exists across individual cells. Emerging single-cell Hi-C (scHi-C) methods now provide direct access to this variability, but their interpretation remains challenging due to the extreme data sparsity. In this thesis, I apply a polymer physics-based framework to infer 3D chromatin architecture from sparse single-cell Hi-C data, bridging the gap between statistical and mechanistic models of genome organization. Using polymer physics models and computational approaches, I reconstruct 3D structures from both bulk and single-cell Hi-C datasets. When applied to experimental scHi-C data, this framework reveals reproducible folding patterns and enables accurate identification of single-cell structural features. Integrating polymer modeling with epigenomic information further uncovers distinct classes of chromatin domains associated with functionally different states, revealing a connection between structural and epigenetic variability. Overall, this work demonstrates that polymer physics provides a quantitative and interpretable framework to explore 3D genome architecture at single-cell resolution, paving the way for future integration with multi-omics and machine-learning approaches to unravel the physical basis of cellular diversity.

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