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Dr. Brock Christensen
Tumors are composed of heterogeneous cell types each with its own unique molecular profiles. Recent advances in single cell genomics technologies have begun to increase our understanding of the molecular heterogeneity that exists in tumors with particular focus on gene expression and chromatin accessibility profiles. However, due to limitations in methods for certain sample types and high cost for single cell genomics, bulk tumor molecular profiling has been and remains widely used. In addition, other facets of single cell epigenomic profiling, particularly methylation and hydroxymethylation, remains underexplored. Thus, investigations to understand the cell type specific epigenetic heterogeneity and the cooperation among various molecular layers to regulate tumorigenesis are needed. In this thesis, I utilize a multi-omic approach integrating DNA methylation, hydroxymethylation, chromatin accessibility, and gene expression profiles to investigate unique single cell type-specific features in 1) epithelial-to-mesenchymal transition and in 2) pediatric central nervous system tumors. First, I demonstrate the shared and distinct epigenetic profiles that are associated with single cells undergoing epithelial-to-mesenchymal transition. With a multi-omic approach, I identify increased hydroxymethylation in binding motifs of transcription factors critical in regulating epithelial-to-mesenchymal transition. Then, I shift my focus to characterize the cellular heterogeneity in pediatric central nervous system tumors and transcriptomic alterations associated with these tumors, while accounting for cell type composition, with single nuclei gene expression data. I detect novel pediatric central nervous system tumor associated genes that are differentially expressed. Finally, I illustrate the cytosine modification alterations that occur predominantly in the progenitorlike cell types of pediatric central nervous system tumors with a multi-omic approach. I determine associations between cell type-specific hydroxymethylation alterations with cell type-specific gene expression changes. Together, these findings emphasize the need for consideration of cellular identity to determine molecular heterogeneity that exist in various cancer contexts. Moreover, these works collectively suggest the utility of multiomic approaches to uncover novel insights in underlying tumor biology.
Lee, Min Kyung, "Characterization of cell type-specific molecular heterogeneity in cancer using multi-omic approaches" (2023). Dartmouth College Ph.D Dissertations. 138.