【原】糖酵解介导的乙酰辅酶A和组蛋白乙酰化的变化控制着胚胎干细胞的早期分化

Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells.

Glycolysis ~ acetyl-CoA ~ histone acetylation(?) ~ pluripotency

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|核心内容：

多能性丧失是一个渐进的过程，其启动因素在很大程度上是未知的。

在这里，我们报道了在分化的最初几个小时内诱导的最早的代谢变化。

高分辨率核磁共振鉴定了44种代谢物，并在早期分化过程中发生了明显的代谢转变。

代谢和转录分析表明，多能细胞通过糖酵解产生乙酰辅酶A，并在分化过程中迅速丧失这一功能。

重要的是，糖酵解的调节阻止了人类和小鼠胚胎干细胞中组蛋白的去乙酰化和分化。

 Acetate Delays Early Differentiation

醋酸盐(acetate)是乙酰辅酶A的前体，它以剂量依赖的方式延迟分化并阻断组蛋白的早期去乙酰化。

乙酰辅酶A上游的抑制剂(乙酰辅酶A减少)诱导多能细胞分化，而下游的抑制剂(乙酰辅酶A积累)延迟分化。(醋酸盐延缓早期分化)

我们的结果显示，在分化的最初几个小时，代谢转换（糖酵解的解除）导致组蛋白乙酰化和多能性状态的丧失。

我们的数据强调了代谢在多能性中的重要作用，并表明控制组蛋白乙酰化的糖酵解开关可以将干细胞从多能性中释放出来。

原文摘要：

Loss of pluripotency is a gradual event whose initiating factors are largely unknown. Here we report the earliest metabolic changes induced during the first hours of differentiation. High-resolution NMR identified 44 metabolites and a distinct metabolic transition occurring during early differentiation. Metabolic and transcriptional analyses showed that pluripotent cells produced acetyl-CoA through glycolysis and rapidly lost this function during differentiation. Importantly, modulation of glycolysis blocked histone deacetylation and differentiation in human and mouse embryonic stem cells. Acetate, a precursor of acetyl-CoA, delayed differentiation and blocked early histone deacetylation in a dose-dependent manner. Inhibitors upstream of acetyl-CoA caused differentiation of pluripotent cells, while those downstream delayed differentiation. Our results show a metabolic switch causing a loss of histone acetylation and pluripotent state during the first hours of differentiation. Our data highlight the important role metabolism plays in pluripotency and suggest that a glycolytic switch controlling histone acetylation can release stem cells from pluripotency.

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● 总结 ●

1. 胚胎干细胞的新陈代谢在分化小时内发生了变化

2. 糖酵解产生的乙酰辅酶 A 促进组蛋白乙酰化的多能性

3. 糖酵解抑制导致多能细胞去乙酰化（转录活性降低）和分化；（DNA复制的模板是DNA，但是转录的模板其实是染色质，包括被修饰的DNA和被修饰的核小体组蛋白H2A,H2B,H3,H4）

4. 乙酰辅酶 a 的药理调节对多能性有调节作用

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参考文献：http://meshorerlab./papers/Moussaieff2015.pdf

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