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Computational Studies of the Three-Dimensional Architecture of Genome Open Access

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In the nucleus, DNA associates with histones to form chromatin that is highly organized in space. Epigenetic regulators, proteins that read, write and erase information encoded in chromatin, have been found to control gene expression. In addition, recent studies revealed that the 3-Dimensional (3D) organization of genome adds an additional layer of regulation to gene expression. My dissertation research focuses on developing and applying novel computational methods to study how the 3D genome architecture and epigenetic regulators play a role in the gene regulation underlying cell-type specificity and cell fate decisions.CTCF is a master regulator of the 3D genome organization. In the research projects leading to this dissertation, I carried out comprehensive analysis of the experimentally identified CTCF-mediated chromatin loops in multiple cell-types. I found that CTCF-mediated loops exhibit extensive plasticity across cell-types. Furthermore, the cell-type specific loops are functionally important, contributing to cell-identity. Motivated by these results, I developed a machine-learning-based computational framework, named Lollipop, to predict the CTCF loops using genomic and epigenomic features. Leveraging the predictive power of our method, I made de novo predictions of CTCF loops in multiple cell-types and performed network analysis of the CTCF-mediated chromatin interactome. I found that CTCF-mediated interactome demonstrates distinct topological properties from the chromatin interaction network mediated by RNA-PolII, the molecular machine carrying out transcription. Inside the 3D nuclear space, epigenetic regulators are important to the regulation of gene expression in development and disease. By integrating high throughput biological data, I studied the roles of two epigenetic regulators, KDM2B (eraser of the di-methylation signal on histone H3 lysine 36) and KDM6A (eraser of the tri-methylation signal on H3 lysine 27). We found that KDM2B cooperates with PcG and TrxG proteins to regulate gene expression programs that determine cellular identity in hematopoietic system. In addition, we identified the KDM6A-driven gene regulatory networks that drive an aggressive subset of pancreatic cancer.In summary, my work in CTCF-mediated chromatin interactions and epigenetic regulators contributes to understanding mechanisms of gene regulation underscoring cell identity.

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