Chemical Modulation of Protein O-GlcNAcylation via OGT Inhibition Promotes Human Neural Cell Differentiation.
Chemical Modulation of Protein O-GlcNAcylation via OGT Inhibition Promotes Human Neural Cell Differentiation.
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DOI：
10.1021/acschembio.7b00232
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发表时间：
2017-08-18
影响因子：
4
通讯作者：
Bertozzi CR
中科院分区：
文献类型：
--
作者：
Andres LM;Blong IW;Evans AC;Rumachik NG;Yamaguchi T;Pham ND;Thompson P;Kohler JJ;Bertozzi CR
决定蛋白质O-GlcNAc化的酶，O-GlcNAc转移酶（OGT）和O-GlcNAc酶（OGA），作用于关键的转录和表观遗传调节因子，并且两者都在脑中大量表达。然而，很少有人知道如何改变O-GlcNAc循环影响人胚胎干细胞（hESC）的神经分化。在这里，我们研究了使用OGT的代谢抑制剂，全乙酰化5-硫代-N-乙酰葡糖胺（Ac 4 - 5SGIcNAc）在hESC神经诱导过程中干扰O-GlcNAc化的影响。在诱导过程中用Ac 4 -5SGlcNAc处理hESC限制了蛋白质O-GlcNAc化，并且还引起UDP-GlcNAc的总体水平的显著降低。同时，神经祖细胞（NPC）的亚群获得了未成熟的神经元形态，并表达早期神经元标记物，如β-III微管蛋白（TUJ 1）和微管相关蛋白2（MAP 2），这些表型在不存在OGT抑制的情况下需要更长时间才能表现出来。这些数据表明，OGT的化学抑制和蛋白质O-GlcNAc化的扰动加速了hESC沿着神经元谱系的分化，从而提供了对神经元发育中涉及的动态分子机制的进一步了解。
The enzymes that determine protein O-GlcNAcylation, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), act on key transcriptional and epigenetic regulators, and both are abundantly expressed in the brain. However, little is known about how alterations in O-GlcNAc cycling affect human embryonic stem cell (hESC) neural differentiation. Here, we studied the effects of perturbing O-GlcNAcylation during neural induction of hESCs using the metabolic inhibitor of OGT, peracetylated 5-thio-N-acetylglucosamine (Ac4-5SGlcNAc). Treatment of hESCs with Ac4-5SGlcNAc during induction limited protein O-GlcNAcylation and also caused a dramatic decrease in global levels of UDP-GlcNAc. Concomitantly, a subpopulation of neural progenitor cells (NPCs) acquired an immature neuronal morphology and expressed early neuronal markers such as β-III tubulin (TUJ1) and microtubule associated protein 2 (MAP2), phenotypes that took longer to manifest in the absence of OGT inhibition. These data suggest that chemical inhibition of OGT and perturbation of protein O-GlcNAcylation accelerate the differentiation of hESCs along the neuronal lineage, thus providing further insight into the dynamic molecular mechanisms involved in neuronal development.
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影响因子：
3
作者：
Francisco, Herb;Kollins, Katherine;Varghis, Neal;Vocadlo, David;Vosseller, Keith;Gallo, Gianluca
通讯作者：
Gallo, Gianluca
影响因子：
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DOI：
10.1016/j.bbrc.2011.10.074
发表时间：
2011-11-18
影响因子：
3.1
作者：
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通讯作者：
Lee, Joon H.
影响因子：
16.6
作者：
Hart GW;Slawson C;Ramirez-Correa G;Lagerlof O
通讯作者：
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