Hybrid Cellular Metabolism Coordinated by Zic3 and Esrrb Synergistically Enhances Induction of Naive Pluripotency

Naive pluripotent stem cells (PSCs) utilize both glycolysis and oxidative phosphorylation (OXPHOS) to satisfy their metabolic demands. However, it is unclear how somatic cells acquire this hybrid energy metabolism during reprogramming toward naive pluripotency. Here, we show that when transduced with Oct4, Sox2, and Klf4 (OSK) into murine fibroblasts, Zic3 and Esrrb synergistically enhance the reprogramming efficiency by regulating cellular metabolic pathways. These two transcription factors (TFs) cooperatively activate glycolytic metabolism independently of hypoxia inducible factors (HIFs). In contrast, the regulatory modes of the TFs on OXPHOS are antagonistic: Zic3 represses OXPHOS, whereas Esrrb activates it. Therefore, when introduced with Zic3, Esrrb restores OXPHOS activity, which is essential for efficient reprogramming. In addition, Esrrb-mediated OXPHOS activation is critical for the conversion of primed PSCs into the naive state. Our study suggests that the combinatorial function of TFs achieves an appropriate balance of metabolic pathways to induce naive PSCs. [Display omitted] •Zic3 and Esrrb synergistically enhance somatic cell reprogramming•Zic3 and Esrrb cooperatively bind and activate glycolysis genes•Esrrb activates OXPHOS, but Zic3 represses it•OXPHOS activation enhances reprogramming of EpiSCs Sone et al. show that the transcription factors Zic3 and Esrrb synergistically enhance the reprogramming efficiency of murine fibroblasts transduced with the classic Oct4, Sox2, and Klf4 cocktail to induce naive pluripotency by regulating cellular metabolic pathways. Zic3 and Esrrb achieve a delicate orchestrated balance of glycolysis and oxidative phosphorylation in PSCs.