Mushroom body-specific gene regulation by the SWI/SNF chromatin remodeling complex
Abstract
Over the lifetime of an organism, neurons must establish, remodel, and maintain precise connections in order to form neural circuits that are required for proper nervous system functioning. Disruptions in these processes can lead to neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder. Mutations in genes encoding subunits of the SWI/SNF chromatin remodeling complex have been implicated in ID, yet the role of this complex in neurons is poorly understood. In this project, I established cell-type specific methods to examine the effect of SWI/SNF subunit knockdowns on gene transcription and chromatin structure in the memory-forming neurons of the Drosophila mushroom body (MB) during periods of neuronal remodeling and experience-dependent synaptic plasticity. Combining transcriptome and epigenome profiling of MB neurons at the onset of pupation revealed that the SWI/SNF complex is critical for regulating genes that are essential to MB γ neuron axon pruning during pupation. These genes include the steroid hormone receptor EcR-B1 and members of the ubiquitin proteasome system. Additionally, the SWI/SNF complex was shown to have a stage-specific effect in regulating chromatin accessibility and transcription of genes required during a critical window of experience-dependent synaptic plasticity in juvenile adult flies. Among these were several genes involved in response to stimulus and axon guidance, including: forked end, Calmodulin, and Dichaete, and the gene encoding an actin-binding protein involved in brain development, Ciboulot. This study investigates the neuron-specific gene regulatory role of the SWI/SNF complex. These findings reveal specific roles for the SWI/SNF complex in regulating distinct processes in post-mitotic neurons and provide the groundwork in understanding the effect of chromatin regulation in SWI/SNF-related ID.