TY - JOUR
T1 - RAS Regulates the Transition from Naive to Primed Pluripotent Stem Cells
AU - Altshuler, Anna
AU - Verbuk, Mila
AU - Bhattacharya, Swarnabh
AU - Abramovich, Ifat
AU - Haklai, Roni
AU - Hanna, Jacob H.
AU - Kloog, Yoel
AU - Gottlieb, Eyal
AU - Shalom-Feuerstein, Ruby
N1 - Funding Information:
We thank Prof. Eran Meshorer for providing Rex1-YFP cells and for critical reading of the manuscript and Dr. Victoria Makovski and the interdisciplinary unit of our faculty for the technical support. The research leading to these results (R.S.-F.) has received funding from the European Union's Seventh Framework Program ( FP7/2007-2013 ) under grant agreement no. 618432-MC-Epi-Patho-Stem and from the Ministry of Science, Technology and Space , Israel, the Ministere de L'Education National de L'Enseignement Supérieur de la Recherche ( 3-11985 ), the Israel Science Foundation , and the Bruce & Ruth Rappaport institute .
Funding Information:
We thank Prof. Eran Meshorer for providing Rex1-YFP cells and for critical reading of the manuscript and Dr. Victoria Makovski and the interdisciplinary unit of our faculty for the technical support. The research leading to these results (R.S.-F.) has received funding from the European Union's Seventh Framework Program (FP7/2007-2013) under grant agreement no. 618432-MC-Epi-Patho-Stem and from the Ministry of Science, Technology and Space, Israel, the Ministere de L'Education National de L'Enseignement Sup?rieur de la Recherche (3-11985), the Israel Science Foundation, and the Bruce & Ruth Rappaport institute.
Publisher Copyright:
© 2018 The Author(s)
PY - 2018/3/13
Y1 - 2018/3/13
N2 - 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.
AB - 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.
KW - RAS
KW - cancer
KW - metabolism
KW - naive
KW - pluripotent stem cells
KW - primed
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U2 - 10.1016/j.stemcr.2018.01.004
DO - 10.1016/j.stemcr.2018.01.004
M3 - Article
C2 - 29456180
AN - SCOPUS:85042034151
SN - 2213-6711
VL - 10
SP - 1088
EP - 1101
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 3
ER -