Cancer genomics has revolutionized cancer research by systematic mapping of oncogenic genetic alterations of genes, yet oncogenic epigenetic alterations of regulatory elements away from genes remain elusive. I recently demonstrated that aberrant DNA methylation of CTCF binding sites perturbs chromosomal topology in IDH-mutant glioma and SDH-deficient gastrointestinal stromal tumors (GISTs). Loss of CTCF binding at the boundary between two topologically associating domains disrupts their insulation, leading to oncogene activation. This groundbreaking model links metabolic, epigenetic and topological alterations and demonstrates that they can drive oncogenesis. Aberrant DNA methylation is common in many tumors and therefore epigenetic CTCF disruption may play a role in other cancers, but this has not been studied to date.
Prompted by my findings, recent advances in genome-wide characterization methods and newly available large-scale data, I now propose to systematically uncover the rules of regulation of DNA methylation at CTCF binding sites, and how its disruption in cancer leads to epigenetic heterogeneity and drives oncogenesis. To achieve that, we will develop new statistical models to systematically uncover the rules of regulation of DNA methylation at CTCF binding sites and its impact on topology (Aim 1); uncover mechanisms of epigenetic topological alterations and their role in cancer (Aim 2); and develop computational tools to study intratumor epigenetic heterogeneity to investigate the interplay between different subclones (Aim 3). Taken together, this research program will facilitate a systematic understanding of epigenetic topological alterations and their role in cancer. These are critical goals for the field in order to understand the events that drive cancer, to discover new biomarkers, dependencies and therapeutic strategies, and to inform epigenetic and other personalized therapies.
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