Authors: James Kentro; Erica Larschan; Kate O'Connor-Giles
Affiliation: Brown University, Providence, RI
Keywords: c. synaptogenesis; d. repressors/corepressors
The cellular diversity of the nervous system underlies its ability to respond to stimuli and produce complex behaviors. Neurons form intricate circuits that transmit information by passing signals through synaptic connections. We have found that hundreds of genetically encoded proteins, both common (pan-neuronal) and neuron subtype-specific, that form the structural and functional components of synapses share a temporal pattern of expression that suggests coordinated regulation. However, no mechanism coordinating the expression of these distinct classes of synaptic genes within and across neuronal subtypes is known. Using motif discovery and analysis of chromatin binding data, we have identified a candidate gene regulatory network that may coordinate expression of synaptic genes. DEAF1, linked to intellectual disability and seizures in humans, and pioneer factors GAF and CLAMP are enriched for binding at synaptic genes and are known to interact with chromatin remodelers and other co-repressor or co-activator proteins. In the Drosophila nervous system, we observe a correlation between the timing of initial synaptic gene transcription and substantial increases in chromatin accessibility at synaptic gene promoters that supports a mechanism of coordination through control of the chromatin environment. In clamp null mutants, we find an upregulation of synaptic gene transcription. RNAi-mediated knockdown of DEAF1, driven by pros-Gal4 in immature neurons, results in increased synaptic bouton number at neuromuscular junctions. These data indicate repressive roles for CLAMP and DEAF1, which have been found to physically interact. The pioneer factor GAF has been found to co-regulate many genes in opposition to CLAMP or DEAF1 in other tissues, and may perform a similar role to increase expression of synaptic genes. We predict this gene regulatory network coordinates expression of pan-neuronal and subtype-specific synaptic genes upstream of terminal selectors by controlling chromatin accessibility at synaptic genes to allow the development of shared traits across distinct neuronal fates.