MicroRNA miR-124 controls the choice between neuronal and astrocyte differentiation by fine-tuning Ezh2 expression.
MicroRNA miR-124 controls the choice between neuronal and astrocyte differentiation by fine-tuning Ezh2 expression.
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DOI：
10.1074/jbc.m113.525493
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发表时间：
2014-07-25
期刊：
影响因子：
--
通讯作者：
Su IH
中科院分区：
文献类型：
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作者：
Neo WH;Yap K;Lee SH;Looi LS;Khandelia P;Neo SX;Makeyev EV;Su IH
背景：神经分化过程中Ezh 2表达减少的分子机制尚不清楚。结果：miR-124直接下调Ezh 2表达，促进神经元分化。结论：Ezh 2是miR-124调控神经元分化的重要靶点。重要性：我们的报告代表了理解microRNA/表观遗传调控电路对神经谱系中细胞命运决定的贡献的重大进展。Polycomb group protein Ezh 2是一种组蛋白H3 Lys-27组蛋白甲基转移酶，协调广泛的表观遗传调控程序。已知几种神经系统特异性基因在干细胞中被Ezh 2抑制，并且在神经元分化期间被去抑制。然而，这种调节的分子机制仍然知之甚少。在这里，我们发现Ezh 2水平在神经元分化过程中被脑富集的microRNA miR-124抑制。miR-124在神经母细胞瘤细胞系中的表达足以上调神经系统特异性Ezh 2靶基因的显著部分。另一方面，在经历神经元分化的胚胎癌细胞中miR-124的自然升高的表达与Ezh 2水平的下调相关。重要的是，在P19和胚胎小鼠神经干细胞中，Ezh 2 mRNA的3′-非翻译区（3′-UTR）缺乏功能性miR-124结合位点，而不是野生型Ezh 2 3′-UTR的过表达阻碍了神经元的分化，并促进了星形胶质细胞的特异性分化。总的来说，我们的研究结果揭示了一种分子机制，允许miR-124通过微调关键表观遗传调节因子的表达来平衡替代分化可能性之间的选择。
Background: Molecular mechanisms underlying reduced expression of Ezh2 during neural differentiation are poorly understood. Results: miR-124 directly down-regulates Ezh2 expression to promote neuronal differentiation. Conclusion: Ezh2 is an important target of miR-124 in the context of neuronal differentiation. Significance: Our report represents a significant advance in understanding the contribution of a microRNA/epigenetic regulatory circuitry to cell fate determination in the neural lineage. Polycomb group protein Ezh2 is a histone H3 Lys-27 histone methyltransferase orchestrating an extensive epigenetic regulatory program. Several nervous system-specific genes are known to be repressed by Ezh2 in stem cells and derepressed during neuronal differentiation. However, the molecular mechanisms underlying this regulation remain poorly understood. Here we show that Ezh2 levels are dampened during neuronal differentiation by brain-enriched microRNA miR-124. Expression of miR-124 in a neuroblastoma cells line was sufficient to up-regulate a significant fraction of nervous system-specific Ezh2 target genes. On the other hand, naturally elevated expression of miR-124 in embryonic carcinoma cells undergoing neuronal differentiation correlated with down-regulation of Ezh2 levels. Importantly, overexpression of Ezh2 mRNA with a 3′-untranslated region (3′-UTR) lacking a functional miR-124 binding site, but not with the wild-type Ezh2 3′-UTR, hampered neuronal and promoted astrocyte-specific differentiation in P19 and embryonic mouse neural stem cells. Overall, our results uncover a molecular mechanism that allows miR-124 to balance the choice between alternative differentiation possibilities through fine-tuning the expression of a critical epigenetic regulator.