Understanding how the structure of human chromosomes guides gene expression is an essential goal of developmental and disease biology. Mutations in genome organizing genes are a cause of neurodevelopmental phenotypes – key evidence for the importance of proper genome folding in human brain development and of genome misfolding in brain disorders. These disorders of genome organization (DGOs) represent an important and relatively common class of genetic conditions featuring intellectual disability, epilepsy, microcephaly, and other neurological phenotypes.

Our work has uniquely modeled a subset of these conditions, the cohesinopathies, caused by mutations affecting the genome-organizing cohesin complex. By introducing causal variants into human induced pluripotent stem cells (iPSCs), differentiating these models into neurons, performing analyses of the 3D genome and transcriptome, and developing pre-therapeutic methods, we have made initial discoveries into the molecular pathophysiology of DGOs and suggested that they could be treated.

We aim to further establish mechanistic bases of disease across the DGOs and to attain new insights into the possibility of restoring of genome structure and healthy gene expression in these conditions. Furthermore, we aim to probe the role of genome structure in neuronal differentiation, including its relative importance in establishing vs maintaining transcriptional programs. These goals, and the preliminary data and methods on which they are built, will allow unprecedented insights into the disease biology of an important class of neurodevelopmental disorders. They will advance the possibility of these ‘static’ brain disorders being treatable. Finally, they will generate fundamental knowledge about the spatial organization of the genome and the regulatory purpose it serves.