Kentro James A, Singh Gunjan, Pham Tuan M, Currie Justin, Khullar Saniya, Medeiros Audrey T, Tsiarli Maria, Larschan Erica, O'Connor-Giles Kate M
Department of Molecular Biology, Cell Biology, & Biochemistry, Brown University, Providence, RI, USA.
Department of Neuroscience, Brown University, Providence, RI, USA.
bioRxiv. 2025 Feb 11:2024.10.30.621128. doi: 10.1101/2024.10.30.621128.
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. We find that synaptic genes are broadly and specifically coordinated at the level of transcription across developing nervous systems. How this spatiotemporal coordination is achieved remains an open question. Through genomic and functional studies in , we demonstrate corresponding coordination of chromatin accessibility and identify chromatin regulators DEAF1 and CLAMP as broad repressors of synaptic gene expression outside windows of peak synaptogenesis. Disruption of either factor temporally dysregulates synaptic gene expression across neuronal subtypes, leading to excess synapse formation. We further find that DEAF1, which is linked to syndromic intellectual disability, is both necessary and sufficient to constrain 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.
化学突触是神经系统中主要的通讯位点。突触形成是一个复杂的过程，涉及数百种必须在两个细胞中同时表达的蛋白质。我们发现，在整个发育中的神经系统中，突触基因在转录水平上广泛且特异性地协调表达。这种时空协调是如何实现的仍然是一个悬而未决的问题。通过在[具体研究对象]中的基因组和功能研究，我们证明了染色质可及性的相应协调，并确定染色质调节因子DEAF1和CLAMP是突触发生高峰期之外突触基因表达的广泛抑制因子。破坏任一因子都会在时间上失调跨神经元亚型的突触基因表达，导致突触形成过多。我们进一步发现，与综合征性智力障碍相关的DEAF1对于限制突触形成既必要又充分。我们的研究结果揭示了广泛的时间协调抑制突触基因表达在调节神经元连接中的关键重要性，并确定了两个关键的抑制因子。
