Disruption of genome folding is increasingly recognized as a driver of human disease, yet the underlying mechanisms remain poorly understood. Our lab uses genetic models and patient-derived cells to investigate how chromosome misfolding and compartmentalization defects contribute to developmental syndromes and other pathologies. In particular, we study cohesinopathies such as Cornelia de Lange Syndrome (CdLS), which are caused by mutations in cohesin or its regulators. Cohesin plays a central role in organizing DNA loops and domain boundaries, and loss of proper cohesin activity leads to widespread transcriptional misregulation. We recently identified the kinase GSK3A as a druggable negative regulator of cohesin, raising the exciting possibility that targeting specific cohesin regulators could provide a therapeutic avenue for CdLS and related disorders.
More broadly, our work has revealed that the 3D genome itself is a druggable feature of the genome. We are now exploring strategies to leverage this property to modulate gene function in a targeted way, providing an entirely new entry point for therapeutic intervention. By bridging basic mechanistic insights with disease models, our goal is to establish the foundation for “drugging the 3D genome.” Just as targeting DNA repair pathways transformed cancer therapy, we believe that manipulating chromosome architecture will open entirely new therapeutic strategies across a wide range of disorders.
The Joyce Lab at UPENN 