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.

多能干细胞从初始状态到启动状态的转变以上皮间质转变、从氧化磷酸化到有氧糖酵解的代谢转换以及表观遗传景观的变化为标志。由于这些变化也被视为肿瘤细胞转化的假定标志，我们假设致癌途径可能参与这一过程。我们报告说，RAS 的活性在小鼠胚胎干细胞 (ESC) 的初始状态下受到抑制，并且所有三种 RAS 亚型在 LIF 撤除、胚状体形成或过渡到引发状态诱导的早期分化时均显着激活。活性 RAS 的强制表达和 RAS 抑制表明 RAS 调节多能干细胞中的糖酵解、CADHERIN 表达和抑制性表观遗传标记的表达。总而言之，这项研究表明 RAS 位于早期 ESC 分化的关键连接点，控制着初始细胞启动的关键过程。