Project Summary/Abstract
Nervous system function requires the integration of diverse neuronal subtypes into neural
circuits that elicit thought and behavior. Despite the extensive diversity of neuronal subtypes, all
neurons share key features, including chemical synapses. Current models indicate that shared
neuronal genes, including pan-synaptic genes, are independently regulated by different
combinations of transcription factors in distinct neuronal subtypes, whereas subtype-specific
synaptic genes are regulated by specific transcription factors called terminal selectors. Our data
demonstrate that pan-neuronal and subtype-specific synaptic genes are temporally coordinated
during synaptogenesis. We have identified a candidate gene regulatory network (GRN) that
includes two known pioneer factors, and propose a model in which positive and negative
regulation of chromatin accessibility underlie the coordinated regulation of synaptic gene
expression to promote synapse formation. In Aim 1, we propose genomic and in vivo functional
validation to test the model that two of our candidate transcription factors, GA-rich motif binding
factors CLAMP and GAGA factor, bind to the same promoters of synaptic genes to exert
opposite effects on chromatin accessibility and transcription. In Aim 2, we propose a
comprehensive and unbiased approach to identifying the GRNs underlying coordinated synaptic
gene expression through single-nucleus RNA- and ATAC-Seq. Successful completion of these
studies will advance our understanding of how the development of shared neuronal traits is
coordinated with cell fate acquisition, and may inform neuronal reprogramming of stem cells.
