α-酮戊二酸对多能性和生殖细胞命运的代谢调节

Metabolic regulation of pluripotency and germ cell fate through α-ketoglutarate.

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|核心内容：

新陈代谢和细胞特性之间的复杂联系正变得越来越明显。

在这里，我们探索了小鼠早期胚胎发育模型中这种联系的基础：从幼稚的多能性到原始生殖细胞(PGCs)的规范。

利用单细胞RNA-SEQ的统计建模和能量代谢调节，我们证明了氧化线粒体代谢在naive多能性中的功能作用。

我们将线粒体三羧酸循环活性与IDH2介导的α-酮戊二酸的产生联系起来，并通过它与关键的表观遗传调节因子的活性联系起来。

因此，这种代谢物在维持PGC的naive多能性和分化过程中起着重要作用，可能是通过维持PGC命运的暂态发育能力的特定组蛋白甲基化状态来实现的。

在PGC的分化过程中，这种代谢产物可能是通过维持特定的组蛋白甲基化状态来维持PGC命运的发育能力的。

我们揭示了能量代谢与生殖细胞发育轨迹中细胞状态转换的表观遗传控制之间的联系，并建立了一个通过代谢调节来稳定短暂细胞状态的范式。

原文摘要：

An intricate link is becoming apparent between metabolism and cellular identities. 

Here, we explore the basis for such a link in an model for early mouse embryonic development: from naïve pluripotency to the specification of primordial germ cells (PGCs). 

Using single-cell RNA-seq with statistical modelling and modulation of energy metabolism, we demonstrate a functional role for oxidative mitochondrial metabolism in naïve pluripotency. 

We link mitochondrial tricarboxylic acid cycle activity to IDH2-mediated production of alpha-ketoglutarate and through it, the activity of key epigenetic regulators. Accordingly, this metabolite has a role in the maintenance of naïve pluripotency as well as in PGC differentiation, likely through preserving a particular histone methylation status underlying the transient state of developmental competence for the PGC fate. We reveal a link between energy metabolism and epigenetic control of cell state transitions during a developmental trajectory towards germ cell specification, and establish a paradigm for stabilizing fleeting cellular states through metabolic modulation.

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参考文献：10.15252/embj.201899518

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