Nuclear Localization of Mitochondrial TCA Cycle Enzymes as a Critical Step in Mammalian Zygotic Genome Activation.
Nuclear Localization of Mitochondrial TCA Cycle Enzymes as a Critical Step in Mammalian Zygotic Genome Activation.
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DOI：
10.1016/j.cell.2016.12.026
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发表时间：
2017-01-12
期刊：
影响因子：
64.5
通讯作者：
Banerjee U
中科院分区：
文献类型：
--
作者：
Nagaraj R;Sharpley MS;Chi F;Braas D;Zhou Y;Kim R;Clark AT;Banerjee U
转录控制需要由线粒体三羧酸（TCA）循环代谢产物指导的表观遗传变化。在小鼠胚胎中，在2细胞阶段的合子基因组激活（ZGA）期间发生全局表观遗传变化。丙酮酸对于超过这一阶段的发育是必不可少的，这与线粒体在这一时期的低活性不一致。我们现在表明，一些酶活性的线粒体酶与TCA循环至关重要的表观遗传重塑是短暂的，部分定位于细胞核。丙酮酸对于这种核定位是必不可少的，并且TCA循环酶进入核的失败与特定组蛋白修饰的丢失和ZGA中的阻断相关。然而，在后期阶段，这些酶仅限于线粒体。在人类中，丙酮酸脱氢酶在4/8-细胞阶段是瞬时核的，与人类胚胎基因组激活的时间一致，表明早期植入前发育的保守代谢控制机制。
Transcriptional control requires epigenetic changes directed by mitochondrial tricarboxylic acid (TCA) cycle metabolites. In the mouse embryo, global epigenetic changes occur during the zygotic genome activation (ZGA) at a 2-cell stage. Pyruvate is essential for development beyond this stage, which is at odds with the low activity of mitochondria in this period. We now show that a number of enzymatically active mitochondrial enzymes associated with the TCA cycle essential for epigenetic remodeling are transiently and partially localized to the nucleus. Pyruvate is essential for this nuclear localization, and a failure of TCA cycle enzymes to enter the nucleus correlates with loss of specific histone modifications and a block in ZGA. At later stages, however, these enzymes are exclusively mitochondrial. In humans, the enzyme pyruvate dehydrogenase is transiently nuclear at the 4/8-cell stage coincident with timing of human embryonic genome activation, suggesting a conserved metabolic control mechanism underlying early pre-implantation development.