RAS Regulates the Transition from Naive to Primed Pluripotent Stem Cells

The transition from naive to primed state of pluripotent stem cells is hallmarked by epithelial-mesenchymal transition, metabolic switch from oxidative phosphorylation to aerobic glycolysis, and changes in the epigenetic landscape. Since these changes are also seen as putative hallmarks of neoplastic cell transformation, we hypothesized that oncogenic pathways may be involved in this process. We report that the activity of RAS is repressed in the naive state of mouse embryonic stem cells (ESCs) and that all three RAS isoforms are significantly activated upon early differentiation induced by LIF withdrawal, embryoid body formation, or transition to the primed state. Forced expression of active RAS and RAS inhibition have shown that RAS regulates glycolysis, CADHERIN expression, and the expression of repressive epigenetic marks in pluripotent stem cells. Altogether, this study indicates that RAS is located at a key junction of early ESC differentiation controlling key processes in priming of naive cells. Altshuler et al. report that RAS activation positively regulated key processes of naive-primed transition of mouse embryonic stem cells, including changes in metabolism, chromatin remodeling, and the switch in CADHERIN expression. Pharmacological inhibition of RAS attenuated cellular priming, suggesting that RAS inhibition may be potentially useful for converting human cells into ground state and for efficient somatic cellular reprogramming.