Modeling of chromatin architecture: implications in health and disease

In eukaryotic cells, the long linear sequence of DNA is packed tightly inside the nucleus in a non-random folded fashion. This organization is formed via the interactions of chromatin with itself and with other nuclear substructures. However, this spatial organization is not static: inside the nucleus, chromatin is subjected to various active forces and thermal noise that produce structural dynamics. As a result, an ensemble of three-dimensional structures are produced both temporally and spatially. Several studies have been performed to characterize the structural properties of the chromatin by analyzing the population-averaged mean structure, but the properties of the chromatin conformational ensemble have not received equal attention. For example, it is not clear how the structural ensemble varies from one cell type to another. Or, how the structural ensemble is transformed during different biological processes such as the cell cycle. Therefore, in this dissertation, I focused on characterizing the structural and dynamical properties of the chromatin structural ensemble at different resolutions ranging from individual chromosomes to local regions. I started my work by developing a computational method to infer the radial distribution of chromosome territories inside the nucleus based on chromosome contact data and genome intrinsic properties (Chapter 1). Next, I moved on to analyze single-cell chromatin conformational data to characterize the degree of variation present in chromosome structural ensemble (Chapter 2). In Chapter 3, I characterized the transition of the structural ensemble during different conditions through contact correlation analysis. After characterizing different properties of the structural ensemble, I focused on the role of the three-dimensional genome organization in different physiological and pathological conditions. In Chapter 4, I studied the relationship between the lamina-associated domains, genomic compartmentalization, and gene expression across different cell types by integrating different genomic data. And, in the final project, I characterized chromosome structural properties associated with different subtypes of breast cancer and breast cancer metastasis to distant organ (Chapter 5). Overall, findings through these projects help to characterize the structural and dynamical properties of chromosome ensemble and how these are altered during different conditions.