Histone methyltransferase enhancer of zeste homolog 2 regulates Schwann cell differentiation
Histone methyltransferase enhancer of zeste homolog 2 regulates Schwann cell differentiation
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DOI：
10.1002/glia.22388
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发表时间：
2012-11-01
期刊：
影响因子：
6.2
通讯作者：
Kuery, Patrick
中科院分区：
文献类型：
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作者：
Heinen, Andre;Tzekova, Nevena;Kuery, Patrick
表观遗传控制对包括少突胶质细胞在内的多种细胞的分化至关重要，少突胶质细胞是中枢神经系统的髓鞘胶质细胞。然而，关于表观遗传因素在周围神经系统成熟中的作用的研究才刚刚兴起。在这里，我们首次展示了组蛋白甲基转移酶，由Zust Homolog 2(EZH2)基因增强子编码，对雪旺细胞分化的影响。在坐骨神经中，EZH2在雪旺细胞中表达，并在围生期达到高峰。抑制原代培养的大鼠雪旺细胞中EZH2的表达减少了细胞突起的长度。这些形态变化伴随着广泛的基因表达模式的变化，包括髓鞘基因的下调和p57Kip2的诱导，我们最近发现p57Kip2是雪旺细胞成熟的内在抑制调节因子。此外，我们还发现，在背根神经节共培养中抑制EZH2会干扰体外髓鞘形成。染色质免疫沉淀分析显示，EZH2结合在p57Kip2启动子上，并减少了组蛋白H3K27三甲基化对基因的抑制。抑制EZH2对形态和髓鞘基因的依赖作用可以被p57Kip2的伴随抑制所逆转，表明p57Kip2是EZH2的下游效应因子。此外，我们描述了Hes5是雪旺细胞中髓鞘基因的转录抑制因子，它是由EZH2抑制诱导的，并在p57Kip2抑制的雪旺细胞中下调。因此，我们已经确定了组蛋白甲基化和雪旺细胞分化控制之间的分子联系，并证明了这种表观遗传机制对神经胶质细胞分化的进行至关重要。(C)2012年威利期刊公司。
Epigenetic control is crucial for the differentiation of a variety of cells including oligodendrocytes, the myelinating glial cells of the central nervous system. However, studies about the implication of epigenetic factors in peripheral nervous system maturation are just emerging. Here, we demonstrate for the first time the impact of a histone methyltransferase, encoded by the enhancer of zeste homolog 2 (EZH2) gene, on Schwann cell differentiation. In sciatic nerves, EZH2 expression was found in Schwann cells and to peak perinatally. Suppression of EZH2 expression in cultured primary rat Schwann cells reduced the length of cell processes. These morphological changes were accompanied by widespread alterations in the gene expression pattern, including downregulation of myelin genes and induction of p57kip2, which we have recently identified as an intrinsic inhibitory regulator of Schwann cell maturation. In addition, we show that EZH2 suppression in dorsal root ganglion cocultures interferes with in vitro myelination. Chromatin immunoprecipitation analysis revealed binding of EZH2 at the p57kip2 promoter and reduction of histone H3K27 trimethylation upon gene suppression. EZH2 suppression-dependent effects on morphology and myelin genes could be reversed by concomitant suppression of p57kip2, indicating that p57kip2 is a downstream effector of EZH2. Furthermore, we describe Hes5 as transcriptional repressor of myelin genes in Schwann cells, which was induced upon EZH2 suppression and downregulated in p57kip2-suppressed Schwann cells. Therefore, we have identified a molecular link between histone methylation and control of Schwann cell differentiation and demonstrate that this epigenetic mechanism is crucial for glial differentiation to proceed. (c) 2012 Wiley Periodicals, Inc.