As the importance of various chromatin remodelers during early human development has become apparent, the biological explanation of why perturbations of these remodelers impact particular developmental process- es, specifically craniofacial development, remains a mystery. In fact, a number of chromatin remodelers, in- cluding Snf2-related CREBBP activator protein (SRCAP), are associated with human craniofacial disorders. Truncation mutations in the SRCAP gene have recently been shown to be the causative mutations in a disor- der called Floating-Harbor syndrome (FHS). Intriguingly, the many symptoms of FHS could be explained by the perturbation of a single population of cells - the neural crest. The neural crest is a transient population of mi- gratory cells arising from the dorsal part of the neural tube during weeks three to six of embryogenesis, making it exceeding difficult to study these cells in a human embryo. To address this issue, our lab has established an in vitro model of human neural crest differentiation, which, together with animal models, can be effectively used to study the biology of the neural crest. However, because neural crest cells contribute to such diverse tissues and organs, including craniofacial structures, they must demonstrate remarkable developmental plasticity and migratory potential, which requires careful execution of transcriptional programs. Indeed, neural crest cells ap- pear highly sensitive to even modest transcriptional perturbations, as mutations in many chromatin remodelers manifest in malformations of neural crest-derived craniofacial structures. SRCAP is known to play a significant role in the precise regulation of transcriptional programs as a part of a protein complex that facilitates active transcription by replacing the canonical H2A-H2B histone dimer with histone variant H2A.Z at transcription start sites and enhancers. The cellular origin of FHS leading to craniofacial defects has not previously been established, and the combination of an in vitro neural crest differentiation model and a high-throughput Xenopus lelvels animal model allows us to study this disorder at multiple levels, from molecular mechanism to cellular defects to disease state. We have recapitulated SRCAP FHS truncations both an in vivo embryological model that displays craniofacial dysmorphology consistent with the syndrome, as well as an in vitro cellular model. Proposed research will take advantage of these models to identify the underlying molecular, cellular, and developmental causes of FHS, thus providing potential targets for treatment. Ultimately, our research will contribute to a biological explanation for why perturbations of chromatin remodelers have such a pronounced impact on craniofacial development.