Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells.
Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells.
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DOI：
10.1038/nature13981
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发表时间：
2015-02-19
期刊：
影响因子：
64.8
通讯作者：
Thompson, Craig B.
中科院分区：
文献类型：
--
作者：
Carey, Bryce W.;Finley, Lydia W. S.;Cross, Justin R.;Allis, C. David;Thompson, Craig B.
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性谷氨酰胺补充的情况下无法增殖，尽管谷氨酰胺是一种非必需氨基酸。本研究表明，在维持初始多能性的条件下生长的小鼠胚胎干细胞（ES）在缺乏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，胚胎干细胞消耗高水平的外源谷氨酰胺。与分化程度更高的细胞相比，初始胚胎干细胞同时利用葡萄糖和谷氨酰胺分解代谢来维持细胞内α-酮戊二酸（αKG）的高水平。因此，初始胚胎干细胞表现出αKG /琥珀酸比值升高，从而促进组蛋白/DNA去甲基化并维持多能性。直接操纵细胞内α - kg /琥珀酸比值足以调节多种染色质修饰，包括H3K27me3和10 - 11易位（Tet）依赖的DNA去甲基化，这有助于调节多能性相关基因的表达。在体外，补充细胞渗透性α - kg直接支持es细胞自我更新，而细胞渗透性琥珀酸促进分化。这项研究表明，细胞内αKG/琥珀酸水平可以促进细胞身份的维持，并在干细胞的转录和表观遗传状态中发挥机制作用。
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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