RAS Regulates the Transition from Naive to Primed Pluripotent Stem Cells

• Published in: Stem cell reports Vol. 10; no. 3; pp. 1088 - 1101
• Main Authors: Altshuler, Anna, Verbuk, Mila, Bhattacharya, Swarnabh, Abramovich, Ifat, Haklai, Roni, Hanna, Jacob H., Kloog, Yoel, Gottlieb, Eyal, Shalom-Feuerstein, Ruby
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-03-2018; Elsevier
• Subjects: Animals; Biomarkers - metabolism; cancer; Cell Differentiation - physiology; Cells, Cultured; Embryoid Bodies - metabolism; Embryoid Bodies - physiology; Epigenesis, Genetic - physiology; metabolism; Mice; Mouse Embryonic Stem Cells - metabolism; Mouse Embryonic Stem Cells - physiology; naive; pluripotent stem cells; Pluripotent Stem Cells - metabolism; Pluripotent Stem Cells - physiology; primed; Protein Isoforms - metabolism; RAS; ras Proteins - metabolism; Signal Transduction - physiology; metabolism; cancer; primed; pluripotent stem cells; RAS; naive
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2018.01.004

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.
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•RAS is activated upon early differentiation of mouse embryonic stem cells (mESCs)•RAS repression by LIF prevents early differentiation•RAS regulates the transition from naive to primed state of mESCs•RAS regulates glycolysis, chromatin remodeling, and CADHERIN expression
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.