Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA.
Dev Cell. 2018 Jul 2;46(1):73-84.e7. doi: 10.1016/j.devcel.2018.06.007.
The ability to convert human somatic cells efficiently to neurons facilitates the utility of patient-derived neurons for studying neurological disorders. As such, ectopic expression of neuronal microRNAs (miRNAs), miR-9/9 and miR-124 (miR-9/9-124) in adult human fibroblasts has been found to evoke extensive reconfigurations of the chromatin and direct the fate conversion to neurons. However, how miR-9/9-124 break the cell fate barrier to activate the neuronal program remains to be defined. Here, we identified an anti-neurogenic function of EZH2 in fibroblasts that acts outside its role as a subunit of Polycomb Repressive Complex 2 to directly methylate and stabilize REST, a transcriptional repressor of neuronal genes. During neuronal conversion, miR-9/9-124 induced the repression of the EZH2-REST axis by downregulating USP14, accounting for the opening of chromatin regions harboring REST binding sites. Our findings underscore the interplay between miRNAs and protein stability cascade underlying the activation of neuronal program.
高效地将人类体细胞转化为神经元，为研究神经疾病患者源性神经元的应用提供了便利。因此，在成人成纤维细胞中异位表达神经元 microRNA（miRNA）miR-9/9 和 miR-124（miR-9/9-124）已被发现可引起染色质的广泛重排，并直接将命运转化为神经元。然而，miR-9/9-124 如何打破细胞命运障碍来激活神经元程序仍有待确定。在这里，我们确定了 EZH2 在成纤维细胞中的一种抗神经发生功能，它作为 Polycomb 抑制复合物 2 的亚基发挥作用，直接甲基化并稳定 REST，即神经元基因的转录抑制因子。在神经元转化过程中，miR-9/9-124 通过下调 USP14 诱导 EZH2-REST 轴的抑制，导致含有 REST 结合位点的染色质区域开放。我们的研究结果强调了 miRNA 和蛋白质稳定性级联反应在激活神经元程序中的相互作用。
