Normally, our chromosomes are divided to multiple topological domains that allow frequent interactions within each domain, but limit the interactions across domain boundaries. We have previously demonstrated that aberrant DNA methylation of CTCF binding sites perturbs chromosomal topology in IDH mutant glioma (Flavahan*, Drier* et al. Nature 2016) and SDH deficient gastrointestinal stromal tumors (Flavahan*, Drier* et al. Nature 2019). We demonstrated that in these tumors, CTCF binding sites at boundaries get methylated, lose CTCF binding, disrupt insulation between adjacent topological domains, and allow aberrant interactions between genes and enhancers. Specifically, this allows activation of the PDGFRA oncogene in gliomas and FGF3, FGF4 and KIT in gastrointestinal stromal tumors, and therefore promote tumorigenesis. This groundbreaking model demonstrates that epigenetic and topologic alterations can drive cancer, while highlighting the importance of regulatory DNA alterations.

We are extending this framework to additional types of cancer and of topologic disruptions to test the interplay between metabolism, epigenetics, topology and gene regulation, and how it is dysregulated across different types of cancer.