Cohesin plays a key role in regulating gene expression by forming DNA loops that connect genes to distal enhancers. Mutations in the structural and regulatory components of the cohesin complex lead to complex developmental disorders and cancers and are associated with chromatin misfolding and widespread gene misexpression. These disorders are collectively referred to as “cohesinopathies” of which Cornelia de Lange Syndrome (CdLS) is the archetype. CdLS is a rare developmental disorder characterized by congenital abnormalities, intellectual disability, and multi-system clinical symptoms including congenital heart disease. 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 cohesin and looping can lead to gene misexpression and ultimately disease are not well understood.
We have several projects underway that 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 dysregulated in patients affected by CdLS.