Uncovering Molecular Determinants of Pathogenic Non-Coding Structural Variation in Leukemia Genomes

Non-coding structural variants (SVs) can rewire chromatin topologies to cause oncogene activation in cancer genomes, yet the molecular determinants for the transcriptional output mediated by SVs remain poorly understood. Advances in sequencing methodologies are increasing the number of SVs identified yet challenges remain to distinguish non-coding SV cancer drivers from non-functional passenger mutations. Hence, deciphering the regulatory principles governing how SVs, epigenetic landscapes, and 3D genome structure cooperate to control oncogenic transcription will be crucial for understanding the pathogenic potential of non-coding SVs. This dissertation outlines the development and implementation of a novel multimodal strategy to detect non-coding SVs with potential functional consequence and the characterization of an interdependency between genetic and chromatin variation for SV-mediated transcriptional effects. Together, these findings broaden our understanding of the features controlling the transcriptional output of pathogenic non-coding SVs and highlight new opportunities to reprogram gene regulation as epigenetic therapies in human disease.