【原】细胞内α-酮戊二酸维持胚胎干细胞的多能性

Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells.

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|核心内容：

细胞代谢在调节细胞增殖和分化中的作用仍然知之甚少。

例如，大多数哺乳动物细胞在没有外源谷氨酰胺补充的情况下无法增殖，即使谷氨酰胺是一种非必需氨基酸。

在这里，我们展示了在保持幼稚多能性的条件下生长的小鼠胚胎干细胞(ES)在没有外源谷氨酰胺的情况下能够增殖。

尽管如此，当代谢物可用时，ES细胞会消耗高水平的外源性谷氨酰胺。

与分化程度较高的细胞相比，幼稚ES细胞利用葡萄糖和谷氨酰胺的分解代谢来维持细胞内高水平的酮戊二酸(α-ketoglutarate，α-KG)。

因此，幼稚的ES细胞表现出较高的DNAKG与琥珀酸的比率，从而促进组蛋白/α去甲基化，并保持多能性。

直接操纵细胞内αKG/琥珀酸比值足以调节多种染色质修饰，包括H3K27me3和依赖于Tet的Tet去甲基化，这有助于调节多能性相关基因的表达。

在体外，补充细胞透性的αKG直接支持ES细胞的自我更新，而细胞透性的琥珀酸则促进分化。

这项工作表明，细胞内αKG/琥珀酸水平有助于维持细胞特性，并在干细胞的转录和表观遗传状态中发挥机械作用。

原文摘要：

The role of cellular metabolism in regulating cell proliferation and differentiation remains poorly understood. For example, most mammalian cells cannot proliferate without exogenous glutamine supplementation even though glutamine is a non-essential amino acid. Here we show that mouse embryonic stem (ES) cells grown under conditions that maintain naive pluripotency are capable of proliferation in the absence of exogenous glutamine. Despite this, ES cells consume high levels of exogenous glutamine when the metabolite is available. In comparison to more differentiated cells, naive ES cells utilize both glucose and glutamine catabolism to maintain a high level of intracellular α-ketoglutarate (αKG). Consequently, naive ES cells exhibit an elevated αKG to succinate ratio that promotes histone/DNA demethylation and maintains pluripotency. Direct manipulation of the intracellular αKG/succinate ratio is sufficient to regulate multiple chromatin modifications, including H3K27me3 and ten-eleven translocation (Tet)-dependent DNA demethylation, which contribute to the regulation of pluripotency-associated gene expression. In vitro, supplementation with cell-permeable αKG directly supports ES-cell self-renewal while cell-permeable succinate promotes differentiation. This work reveals that intracellular αKG/succinate levels can contribute to the maintenance of cellular identity and have a mechanistic role in the transcriptional and epigenetic state of stem cells.

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参考文献：10.1038/nature13981

https:///10.1038/nature13981

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