美国纪念斯隆凯特琳癌症研究所Lorenz Studer等研究人员合作发现，一个表观遗传学屏障设定人类神经元成熟的时间。相关论文于2024年1月31日在线发表于国际学术期刊《自然》。

研究人员发现了一种设定人类神经元成熟时间的表观遗传发育程序。首先，研究人员开发了一种基于人类多能干细胞（hPSC）的方法来同步体外皮层神经元的诞生，这使其能够确定形态、功能和分子成熟的图谱。研究人员观察到，由于特定表观遗传因子的保留，成熟过程缓慢展开。在大脑皮层神经元中，如果这些因子中的几个失去功能，就会导致早熟。在祖细胞阶段短暂抑制EZH2、EHMT1和EHMT2或DOT1L，可使新生神经元在分化后迅速获得成熟特性。

因此，这些研究结果表明，通过在祖细胞中建立表观遗传屏障，人类神经元的成熟速度早在神经发生之前就已确定。从机理上讲，这种屏障将转录成熟程序保持在一种静止状态，然后逐渐释放，以确保人类大脑皮层神经元的成熟时间得以延长。

据了解，与大多数其他物种相比，人类大脑的发育速度非常缓慢。皮层神经元的成熟尤其缓慢，需要数月到数年的时间才能形成成人功能。值得注意的是，由hPSC衍生的大脑皮层神经元在体外分化或移植到小鼠大脑后，仍能保持这种漫长的时间。这些发现表明存在一个细胞内在时钟，它设定了神经元成熟的节奏，尽管这个时钟的分子性质仍然未知。

附：英文原文

Title: An epigenetic barrier sets the timing of human neuronal maturation

Author: Ciceri, Gabriele, Baggiolini, Arianna, Cho, Hyein S., Kshirsagar, Meghana, Benito-Kwiecinski, Silvia, Walsh, Ryan M., Aromolaran, Kelly A., Gonzalez-Hernandez, Alberto J., Munguba, Hermany, Koo, So Yeon, Xu, Nan, Sevilla, Kaylin J., Goldstein, Peter A., Levitz, Joshua, Leslie, Christina S., Koche, Richard P., Studer, Lorenz

Issue&Volume: 2024-01-31

Abstract: The pace of human brain development is highly protracted compared with most other species1,2,3,4,5,6,7. The maturation of cortical neurons is particularly slow, taking months to years to develop adult functions3,4,5. Remarkably, such protracted timing is retained in cortical neurons derived from human pluripotent stem cells (hPSCs) during in vitro differentiation or upon transplantation into the mouse brain4,8,9. Those findings suggest the presence of a cell-intrinsic clock setting the pace of neuronal maturation, although the molecular nature of this clock remains unknown. Here we identify an epigenetic developmental programme that sets the timing of human neuronal maturation. First, we developed a hPSC-based approach to synchronize the birth of cortical neurons in vitro which enabled us to define an atlas of morphological, functional and molecular maturation. We observed a slow unfolding of maturation programmes, limited by the retention of specific epigenetic factors. Loss of function of several of those factors in cortical neurons enables precocious maturation. Transient inhibition of EZH2, EHMT1 and EHMT2 or DOT1L, at progenitor stage primes newly born neurons to rapidly acquire mature properties upon differentiation. Thus our findings reveal that the rate at which human neurons mature is set well before neurogenesis through the establishment of an epigenetic barrier in progenitor cells. Mechanistically, this barrier holds transcriptional maturation programmes in a poised state that is gradually released to ensure the prolonged timeline of human cortical neuron maturation.

DOI: 10.1038/s41586-023-06984-8

Source: https://www.nature.com/articles/s41586-023-06984-8