PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications.
PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications.
复制标题
PI3K/AKT/mTOR 信号传导通过表观遗传修饰介导丙戊酸诱导的神经干细胞的神经元分化
DOI：
10.1016/j.stemcr.2017.04.006
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发表时间：
2017-05-09
影响因子：
5.9
通讯作者：
Xuan A
中科院分区：
文献类型：
--
作者：
Zhang X;He X;Li Q;Kong X;Ou Z;Zhang L;Gong Z;Long D;Li J;Zhang M;Ji W;Zhang W;Xu L;Xuan A
尽管丙戊酸（VPA）已被证明可诱导神经干细胞（NSC）的神经元分化，但其潜在机制仍知之甚少。在这里，我们调查是否以及如何哺乳动物雷帕霉素靶（mTOR）信号参与VPA诱导的神经干细胞的神经元分化。我们的数据表明，mTOR激活不仅促进VPA诱导的神经干细胞的神经元分化，而且是必要的。我们进一步发现，抑制mTOR信号传导阻断了诱导细胞中神经元特异性基因neurogenin 1（Ngn 1）调节元件的去甲基化。这些与Ngn 1启动子中被动DNA去甲基化和主动DNA去甲基化途径的显著改变相关，但与Ngn 1启动子区域中赖氨酸特异性组蛋白甲基化和乙酰化的抑制无关。这些发现强调了mTOR信号传导的潜在重要作用，通过与DNA去甲基化一起作用，通过调节Ngn 1在VPA诱导的NSC神经元分化中的表达来影响NSC的命运。VPA诱导的NSC的神经元分化需要mTOR激活mTOR信号传导参与NSC中Ngn 1的被动和主动DNA去甲基化Dnmts抑制剂挽救由mTOR抑制所阻止的分化Tets敲低消除VPA对NSC的促分化作用在这篇文章中，Aiguo Xuan及其同事表明，PI 3 K/Akt/VPA诱导神经干细胞向神经元分化过程中，mTOR信号参与Ngn 1启动子区被动和主动DNA去甲基化。然而，在分化过程中，Ngn 1调节区的组蛋白修饰的改变不依赖于mTOR通路。
Although valproic acid (VPA), has been shown to induce neuronal differentiation of neural stem cells (NSCs), the underlying mechanisms remain poorly understood. Here we investigated if and how mammalian target of rapamycin (mTOR) signaling is involved in the neuronal differentiation of VPA-induced NSCs. Our data demonstrated that mTOR activation not only promoted but also was necessary for the neuronal differentiation of NSCs induced by VPA. We further found that inhibition of mTOR signaling blocked demethylation of neuron-specific gene neurogenin 1 (Ngn1) regulatory element in induced cells. These are correlated with the significant alterations of passive DNA demethylation and the active DNA demethylation pathway in the Ngn1 promoter, but not the suppression of lysine-specific histone methylation and acetylation in the promoter region of Ngn1. These findings highlight a potentially important role for mTOR signaling, by working together with DNA demethylation, to influence the fate of NSCs via regulating the expression of Ngn1 in VPA-induced neuronal differentiation of NSCs. mTOR activation is required for the neuronal differentiation of NSCs induced by VPA mTOR signaling is involved in passive and active DNA demethylations of Ngn1 in NSCs Dnmts inhibitor rescues differentiation arrested by mTOR inhibition Tets knockdown abolishes the prodifferentiation effect of VPA on NSCs In this article, Aiguo Xuan and colleagues show that PI3K/Akt/mTOR signaling is involved in passive and active DNA demethylation of Ngn1 promoter region in neuronal differentiation of NSCs induced by VPA. However, the alteration of histone modifications in the regulatory region of Ngn1 is independent on mTOR pathway during differentiation.