据介绍，原钙粘蛋白（Pcdh）基因的表达对神经元身份的产生和神经系统的连接至关重要。Pcdhα基因呈簇状排列，表现出从随机到确定性的一系列表达谱。由于Pcdhα启动子具有高度的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尚不清楚。
研究人员发现，多种增强子、表观遗传学和基因组折叠之间的相互作用协调了神经元中基因座的差异读出。Pcdhα启动子选择的概率取决于黏连蛋白催化的增强子/启动子相遇，黏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。
总之，研究人员提出，可调的位点特异性调控元件和细胞类型特异性内聚蛋白活性是Pcdh基因产生细胞多样性的基础。
附：英文原文
Title: Tuning cohesin trajectories enables differential readout of the Pcdhα cluster across neurons
Author: Lea Kiefer, Simon Gaudin, Sandy M. Rajkumar, Gabrielle Isabelle F. Servito, Jennifer Langen, Michael H. Mui, Shayra Nawsheen, Daniele Canzio
Issue&Volume: 2024-07-26
Abstract: 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.
DOI: adm9802
Source: https://www.science.org/doi/10.1126/science.adm9802