BAF complex inhibitors in neuronal development and functions

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PROJECT SUMMARY Neurodevelopmental disorders (NDDs) are becoming more prevalent among our children at an alarming rate. Recent genome-wide studies suggest a strong correlation between NDDs and loss-of-function mutations in genes encoding subunits of the BAF (alias, mSWI/SNF) chromatin remodeling complex. Despite such strong correlative evidence, the precise role(s) of the BAF complex in neurodevelopmental gene transcription remains largely unexplored, in part, due to lack of efficient chemical/pharmacological tools to disrupt BAF function. In response to the NIH funding opportunity titled, ‘Discovery of Cell-based Chemical Probes for Novel Brain Targets’, this project will further develop and test a promising group of BAF inhibitors in maturing rat cortical neurons and use these inhibitors to probe the function of these chromatin remodeling complexes in neuronal activity-induced gene transcription, a key molecular driver of neuronal maturation. Specific aims of this project are: 1) Chemically modify ‘hit’ molecule BAFi to increase potency in neuronal cells, and 2) Determine the role of BAF complex in neurodevelopmentally important activity-induced gene transcription. The project will be conducted simultaneously in two laboratories with long standing expertise in –respectively– development of small molecule inhibitors of chromatin remodelers (the Dykhuizen laboratory at Purdue university; aim 1) and activity-induced neuronal gene transcription (the Saha laboratory at University of California, Merced; aim 2). Taken together, this study will generate valuable chemical tools to study BAF complex functions and deeper insights into epigenetic mechanisms driving normal neurodevelopment, which will fill in the knowledge gap between BAF mutations and their outcomes, such as NDDs.