The Role of Fos and the BAF Complex in Neuronal Activity-Dependent Chromatin Remodeling and Gene Expression - Pediatric neurodevelopmental disorders (NDD), including pediatric epilepsy, autism spectrum disorder, and intellectual disability, represent a major source of morbidity, yet our therapeutic options remain limited. Development of novel therapies for NDD will require a deeper mechanistic understanding of normal and abnormal brain development. This proposal focuses on genetic programs that are activated in response to neuronal activity and that are fundamental to normal neurodevelopment and on-going neuronal plasticity throughout life. Fos is a major activity-dependent transcription factor that binds to distal enhancer elements and regulates downstream activity-dependent genetic programs in a cell-type-specific manner to promote key processes, including synaptic pruning and the recruitment of inhibition in the developing brain. Despite its role in key developmental processes, we do not understand how Fos is differentially targeted to cell-type-specific binding sites, nor how genetic variation at these sites impacts neurodevelopment and neuronal function. Interestingly, Fos has been shown to physically interact with the BAF chromatin remodeling complex, and it is possible that this interaction is critical to Fos function. Many BAF subunits, most frequently ARID1B, are implicated in human NDD, but whether the BAF complex regulates neuronal activity-dependent genetic programs, and how this underlies aspects of BAF complex-related NDD, is previously unexplored. The research in this proposal will address these gaps in knowledge by: (a) profiling Fos and BAF complex neuronal binding sites across the human genome; (b) assessing human genetic variants at these sites in individuals with NDD vs controls; and (c) determining the effects of BAF complex perturbation on neuronal activity-dependent genetic programs in vitro and in vivo. Overall, this work will lead to greater insight into how activity-dependent genetic programs contribute to NDD pathogenesis. Additionally, by identifying specific activity-regulated genes and pathways that are mis-regulated downstream of Fos and the BAF complex, these experiments could highlight novel therapeutic targets for NDD. This research is the basis for a five-year career development program designed to build on Dr. Trowbridge’s background in molecular neuroscience, pediatric neurology/epilepsy, and neurogenetics, by providing her with additional training in analysis of human sequencing data, use of in vitro and in vivo models of NDD, and next- generation sequencing technologies. Her primary mentor, Dr. Mike Greenberg, and her scientific advisory committee, Drs. Annapurna Poduri and Chris Walsh, will provide guidance in these areas, as well as mentorship in the rigorous and ethical conduct of translational neuroscience research. Thus the proposed training plan will position Dr. Trowbridge to launch her independent career as a clinician-scientist focused on understanding the role of activity-dependent genetic programs in NDD.
