Expression of Protocadherin (Pcdh) genes is critical to the generation of neuron identity and wiring of the nervous system. Pcdhα genes are arranged in clusters and exhibit a range of expression profiles, from stochastic to deterministic. Because Pcdhα promoters have high sequence identity and share distal enhancers, how distinct neurons choose which gene to express remains unclear. We show that the interplay between multiple enhancers, epigenetics, and genome folding orchestrates differential readouts of the locus across neurons. The probability of Pcdhα promoter choice depends on enhancer/promoter encounters catalyzed by cohesin, whose extrusion trajectories determine the likelihood that an individual promoter can “escape” heterochromatin-mediated silencing. We propose that tunable locus-specific regulatory elements and cell type–specific cohesin activity underlie the generation of cellular diversity by Pcdh genes.

中文翻译：

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调整粘连蛋白轨迹可以实现跨神经元的 Pcdhα 簇的差异读出


原钙粘蛋白 (Pcdh) 基因的表达对于神经元身份的生成和神经系统的连接至关重要。 Pcdhα 基因排列成簇，并表现出从随机到确定性的一系列表达谱。由于 Pcdhα 启动子具有高度序列同一性并共享远端增强子，因此不同的神经元如何选择表达哪个基因仍不清楚。我们表明，多个增强子、表观遗传学和基因组折叠之间的相互作用协调了神经元基因座的差异读数。 Pcdhα 启动子选择的概率取决于粘连蛋白催化的增强子/启动子相遇，粘连蛋白的挤出轨迹决定了单个启动子可以“逃脱”异染色质介导的沉默的可能性。我们提出可调节位点特异性调控元件和细胞类型特异性粘连蛋白活性是 Pcdh 基因产生细胞多样性的基础。