NANOG governs cell metabolism and redox homeostasis in human naïve embryonic stem cells

Naïve human embryonic stem cells (hESCs) possess some advantages over their primed counterparts, displaying distinctive metabolic and epigenetic properties. However, the master regulator governing these features remains unrecognized. Here, we systematically investigate functions of the core transcription factor NANOG in naïve hESCs. Acting as an upstream key regulator, NANOG directly activates genes associated with naïve pluripotency, acetyl-CoA synthesis and anti-oxidation in a naïve pluripotency state- dependent manner, and represses the expression of extraembryonic lineage genes in naïve hESCs. NANOG modulates transcription of multiple genes in various pathways of acetyl-CoA synthesis, maintains the intracellular acetyl-CoA level and characteristic epigenetic landscapes, particularly the high level of histone acetylation, in naïve hESCs. NANOG is indispensable for the high activity of both OXPHOS and glycolysis, a bivalent metabolic state typical in naïve hESCs. Furthermore, we identify GPX2 as a mediator of NANOG in sustaining redox balance and survival of naïve hESCs. Together, this study reveals previously unrecognized roles of NANOG in orchestrating transcriptional, metabolic and epigenetic signatures to secure human naïve pluripotency.