Conserved transcription factors coordinate synaptic gene expression through repression

Chemical synapses are the primary sites of communication in the nervous system. Synapse formation is a complex process involving hundreds of proteins that must be expressed in two cells at the same time. How this spatiotemporal coordination is achieved remains an open question. We find that synaptic genes are broadly and specifically coordinated at the level of transcription across species. Through genomic and functional studies in Drosophila , we demonstrate corresponding coordination of chromatin accessibility and identify chromatin regulators DEAF1 and CLAMP as broad repressors of synaptic gene expression. Disruption of either factor causes increased synaptic gene expression across neuronal subtypes and excess synapse formation. We further find that DEAF1, which is linked to syndromic intellectual disability, is both necessary and sufficient to repress synapse formation. Our findings reveal the critical importance of broad temporally coordinated repression of synaptic gene expression in regulating neuronal connectivity and identify two key repressors.