Roberta Scognamiglio, Nina Cabezas-Wallscheid, Marc Christian Thier, Sandro Altamura, Alejandro Reyes, Áine M. Prendergast, Daniel Baumgärtner, Larissa S. Carnevalli, Ann Atzberger, Simon Haas, Lisa von Paleske, Thorsten Boroviak, Philipp Wörsdörfer, Marieke A.G. Essers, Ulrich Kloz, Robert N. Eisenman, Frank Edenhofer, Paul Bertone, Wolfgang Huber, Franciscus van der Hoeven, Austin Smith, Andreas Trumpp

Mouse embryonic stem cells (ESCs) are maintained in a naive ground state of pluripotency in the presence of MEK and GSK3 inhibitors. Here, we show that ground-state ESCs express low Myc levels. Deletion of both c-myc and N-myc (dKO) or pharmacological inhibition of Myc activity strongly decreases transcription, splicing, and protein synthesis, leading to proliferation arrest. This process is reversible and occurs without affecting pluripotency, suggesting that Myc-depleted stem cells enter a state of dormancy similar to embryonic diapause. Indeed, c-Myc is depleted in diapaused blastocysts, and the differential expression signatures of dKO ESCs and diapaused epiblasts are remarkably similar. Following Myc inhibition, pre-implantation blastocysts enter biosynthetic dormancy but can progress through their normal developmental program after transfer into pseudo-pregnant recipients. Our study shows that Myc controls the biosynthetic machinery of stem cells without affecting their potency, thus regulating their entry and exit from the dormant state.