Deaf1 regulates the coordinated repression of synaptic genes to limit synaptogenesis

Abstract

Synapses are the primary sites of communication in the nervous system. Synapse formation requires the simultaneous expression of hundreds of proteins across cells. Through genomic and functional studies in Drosophila, we investigated the regulatory mechanisms underlying the spatiotemporal coordination of synaptic gene expression during neurodevelopment. We find that chromatin opening is coordinated across hundreds of synaptic genes immediately preceding transcription, whereas repression of these genes outside developmental periods of synaptogenesis is regulated by distinct mechanisms. We identify the conserved DEAF1 transcription factor (TF) as a direct repressor of synaptic genes. Disruption of DEAF1 or pioneer TF CLAMP, which promotes DEAF1 binding, increases synaptic gene expression across neuronal subtypes, leading to excess synapse formation. DEAF1, which is linked to syndromic intellectual disability, is also sufficient to block synaptogenesis. These findings reveal the importance of coordinated synaptic gene repression in sculpting neuronal connectivity and broaden our understanding of gene regulation in neurodevelopment.