SMC Complexes and Disease

Cornelia de Lange Syndrome (CdLS) is a developmental disorder characterized by congenital abnormalities, intellectual disability, and multi-system clinical symptoms including congenital heart disease. The disorder typically manifests due to mutations in the structural and regulatory components of the cohesin protein complex, and is associated with widespread changes in gene expression. Cohesin is essential to maintain three-dimensional genome organization and structures chromatin into locally self-interacting clusters called topologically associating domains (TADs). The causal role of cohesin in CdLS strongly suggests a functional link between chromatin organization and organismal development. However, the mechanisms by which disruption of TAD structure can lead to gene misexpression and ultimately disease are not well understood.

This project will address this basic gap in knowledge of how members of the cohesin complex regulate genome folding and cellular function and will map how 3D genome topology is disregulated in patients affected by CdLS. The study will be the first to systematically and comprehensively examine the role of the spatial organization of the genome in the pathophysiology of CdLS.