Glycolysis Regulates Human Embryonic Stem Cell Self-Renewal under Hypoxia through HIF-2α and the Glycolytic Sensors CTBPs

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. •Under hypoxic conditions HIF-2α binds an HRE in the CTBP proximal promoters in hESCs•Glycolysis regulates HIF-2α expression in hESCs•CTBPs mediate the activation of pluripotency marker expression in hESCs•Under hypoxia, glycolysis regulates hESC self-renewal through HIF-2α and CTBPs In this article, Houghton and colleagues demonstrate that glycolysis is necessary to maintain human embryonic stem cell (hESC) self-renewal under hypoxic conditions by regulating the expression of HIF-2α and the glycolytic sensors CTBPs. CTBPs are regulated directly by HIF-2α only in hESCs cultured under hypoxia. Inhibiting glycolysis under hypoxic conditions resulted in a decrease in HIF-2α, CTBPs, and pluripotency marker expression.