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Epigenetics plays an important role in cancer development and progression. Cancer cells hijack the epigenome by modifying the histone protein units responsible for packaging DNA, or by modifying the DNA itself, resulting in changes to chromatin topology and transcriptional programming within the cell. In this thesis, I report our investigation to uncover the mechanisms of epigenetic regulation and how epigenetic control of transcriptional programming goes awry in cancer. We investigate these processes in two separate contexts. In our first study, we investigate the mechanisms by which EZH2 oncogenic mutations alter structure and function of topologically associating domains in non-Hodgkin lymphoma. The process of chromatin folding leads to a systematic arrangement of hierarchical structural and regulatory elements found within the nucleus. A topologically associating domain (TAD) is a regulatory unit of self interacting DNA, where the transcription of the genes within a TAD is usually dictated by the presence of active (H3K36me3) or inactive (H3K27me3) histone marks. In cancer, the somatic point mutation in EZH2Y646X leads to a genome wide increase in H3K27me3, associated with transcriptional repression. While this alteration leads to changes in the global epigenetic status of the cell, its impact on chromatin organization and TAD-related function remain unclear. By combining transcriptomics and epigenetics with analyses of chromatin structure, we demonstrate a functional interplay between TADs and the epigenetic and transcriptional program of the genes found within them. This balance is altered by EZH2Y646X, leading to the synergistic silencing of entire domains directly targeting cell differentiation and tumor suppressive programs. A closer look reveals that the silencing of tumor suppressive TADs are coupled with structural modifications and changes in promoter interactions within EZH2Y646X target TAD6.139. Impressively, the TAD’s transcriptional and epigenetic programs are restored by pharmacological inhibition of EZH2Y646X. Our results indicate that EZH2Y646X alters the topology and function of chromatin domains to promote synergistic oncogenic programs. In our second study, we dissect the epigenetic, transcriptomic, and metabolic signaling dependencies using a novel model of central nervous system primitive neural ectodermal tumors (CNS-PNETs). Central nervous system (CNS) tumors are the leading cause of cancer-associated death in children. Primitive neural-ectodermal tumors (CNS-PNETs) are a particularly aggressive subtype of embryonal CNS-tumor, with a five-year overall survival rate in less than 50% of patients. Despite sharing a similar cell of origin of other CNS tumors, CNS-PNETs have a different anatomical location, unique genetic and epigenetic features, and significantly worse clinical outcome. In addition, a lack of in vivo models for studying CNS tumors challenges the opportunity to dissect the genetic variables that underlie the origin of these tumors. We developed a novel CNS-PNET mouse model, called CNS-NPCs, using neural progenitor cells derived from human-iPS cells. Through histological, DNA methylation, and RNA sequencing analyses, we find that the CNS-NPC model recapitulates the the morphologic, epigenetic, and transcriptomic features of primary CNS-PNETs. In addition, through in vivo metabolic analyses of CNS-NPCs and the patient derived cell line, PFSK-1, we identified dysregulation in the neurotransmitter...