Centre for Human Development, Stem Cells and Regeneration, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
Stem Cell Reports. 2019 Apr 9;12(4):728-742. doi: 10.1016/j.stemcr.2019.02.005. Epub 2019 Mar 14.
Glycolysis and hypoxia are key regulators of human embryonic stem cell (hESC) self-renewal, but how changes in metabolism affect gene expression is poorly understood. C-terminal binding proteins (CTBPs) are glycolytic sensors that through NADH binding link the metabolic state of the cell to its gene expression, by acting as transcriptional corepressors, or coactivators. However, the role of CTBPs in hESCs has not previously been investigated. A direct interaction between hypoxia-inducible factor 2α (HIF-2α) and the CTBP proximal promoters in hESCs cultured only under hypoxia was demonstrated. Decreasing the rate of flux through glycolysis in hESCs maintained under hypoxia resulted in a reduction of CTBPs, OCT4, SOX2, and NANOG, but also in the expression of HIF-2α. Silencing CTBP expression resulted in the loss of pluripotency marker expression demonstrating that CTBPs are involved in hESC maintenance. These data suggest that under hypoxia, glycolysis regulates self-renewal through HIF-2α and the induction of the metabolic sensors CTBPs.
糖酵解和缺氧是人类胚胎干细胞（hESC）自我更新的关键调节因素，但代谢变化如何影响基因表达还知之甚少。C 端结合蛋白（CTBPs）是糖酵解的传感器，通过与 NADH 结合，将细胞的代谢状态与其基因表达联系起来，从而作为转录共阻遏物或共激活物发挥作用。然而，CTBPs 在 hESC 中的作用尚未得到研究。研究表明，在仅在低氧条件下培养的 hESC 中，缺氧诱导因子 2α（HIF-2α）与 CTBP 近端启动子之间存在直接相互作用。在维持低氧的 hESC 中降低糖酵解通量的速度会导致 CTBPs、OCT4、SOX2 和 NANOG 的减少，但也会导致 HIF-2α 的表达。沉默 CTBP 的表达导致多能性标记物的表达丧失，表明 CTBPs 参与了 hESC 的维持。这些数据表明，在低氧条件下，糖酵解通过 HIF-2α 和代谢传感器 CTBPs 的诱导来调节自我更新。
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