美国加州大学圣迭戈分校Ivan Garcia-Bassets、Angels Almenar-Queralt等研究人员发现，在多能干细胞由初始到活化的转化过程中，染色质建立起一种未成熟的神经元原钙粘蛋白选择状态。2019年11月18日《自然—遗传学》在线发表了这项成果。

研究人员发现了一种基于染色质的机制，其在从初始到活化的细胞多能性的过渡期间出现，并降低了人类成簇的原钙粘蛋白（cPCDH）基因座的组合潜力。这种机制在单层神经细胞分化、10个月大的皮质类器官体以及大鼠脊髓内移植细胞的神经元分化后，选择性增加一小部分cPCDH基因随机选择的频率。除了在唐氏综合症等延迟成熟的情况下，整个胎儿发育过程中大脑中都可以观察到这些频繁选择的迹象，并且在出生后就消失了。因此，研究人员认为当人类神经元仍保留胎儿样成熟水平时，cPCDH基因表达多样性的限制模式得以维持。

据介绍，在哺乳动物基因组中，cPCDH基因座提供了随机基因表达的模式，并有可能在每个神经元中产生独特的cPCDH组合。

附：英文原文

Title: Chromatin establishes an immature version of neuronal protocadherin selection during the naive-to-primed conversion of pluripotent stem cells

Author: Angels Almenar-Queralt, Daria Merkurjev, Hong Sook Kim, Michael Navarro, Qi Ma, Rodrigo S. Chaves, Catarina Allegue, Shawn P. Driscoll, Andrew G. Chen, Bridget Kohlnhofer, Lauren K. Fong, Grace Woodruff, Carlos Mackintosh, Dasa Bohaciakova, Marian Hruska-Plochan, Takahiro Tadokoro, Jessica E. Young, Nady El Hajj, Marcus Dittrich, Martin Marsala, Lawrence S. B. Goldstein, Ivan Garcia-Bassets

Issue&Volume: 2019-11-18

Abstract: In the mammalian genome, the clustered protocadherin (cPCDH) locus provides a paradigm for stochastic gene expression with the potential to generate a unique cPCDH combination in every neuron. Here we report a chromatin-based mechanism that emerges during the transition from the naive to the primed states of cell pluripotency and reduces, by orders of magnitude, the combinatorial potential in the human cPCDH locus. This mechanism selectively increases the frequency of stochastic selection of a small subset of cPCDH genes after neuronal differentiation in monolayers, 10-month-old cortical organoids and engrafted cells in the spinal cords of rats. Signs of these frequent selections can be observed in the brain throughout fetal development and disappear after birth, except in conditions of delayed maturation such as Down’s syndrome. We therefore propose that a pattern of limited cPCDH-gene expression diversity is maintained while human neurons still retain fetal-like levels of maturation.

DOI: 10.1038/s41588-019-0526-4

Source: https://www.nature.com/articles/s41588-019-0526-4