THE DEVELOPMENTAL LOGIC OF ENHANCEROPATHIES CAUSED BY KMT2D AND YY1 HAPLOINSUFFICIENCY THROUGH PATIENT-DERIVED DISEASE MODELING PLATFORMS

The human brain is generated by developmental events orchestrated by fine-tuned transcriptional events. The vulnerability of this process is highlighted by the fact that environmental insults in early stages of development, or germline mutations in chromatin remodelers, often lead to neurodevelopmental disorders. An historical challenge for studying neurodevelopmental disorders has been the lack of reliable human platforms. Nowadays, technological advancements allowed us to use human cellular models to study the neurons and the molecular implications of specific mutations. In this work is described a human modeling platform of Kabuki Syndrome, caused by germline mutations in the enzyme KMT2D, which is involved in enhancer activation, and of Gabriele-de Vries syndrome, caused by mutations in YY1, which mediates DNA looping between gene promoters and enhancers. These two diseases thus belong to the class of enhanceropathies. Using induced pluripotent stem cells and their differentiation in disease-relevant cell types such as neural crest stem cells and cortical excitatory neurons, it was possible to identify molecular and functional phenotypes unique to Kabuki syndrome that contribute to the understanding of its molecular pathogenesis. Moreover, starting from genetic observations of individuals with intellectual disabilities who lacked a molecular diagnosis, YY1 was identified as the mutated gene responsible for a novel neurodevelopmental disorder, which is caused by an improper regulation of transcriptional enhancers. The synergic study of enhanceropathies may lead to the identification of altered gene regulatory networks, convergent to common targets, responsible for shared clinical features, thus paving the way for the identification of shared actionable pathways.