Myc Depletion Induces a Pluripotent Dormant State Mimicking Diapause

Abstract

SummaryMouse 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.

Pro‑metastatic signaling of the trans fatty acid elaidic acid is associated with lipid rafts

“…c-Myc is associated with cell proliferation and aerobic glycolysis, and PGC-1A is associated with stemness and oxidative phosphorylation (21,22). The upregulation of nanog in the present data and our previous data (5) indicated that EA increased the stemness of cancer cells; however, the cancer cells may have been of a proliferative nature with glycolytic energy metabolism, which is different from dormant stem cells that possess oxidative phosphorylation metabolism.…”

Cycling through developmental decisions: how cell cycle dynamics control pluripotency, differentiation and reprogramming

“…The developmental state of pluripotent cells can also be regulated by exit from the cell cycle. For example, PSCs exit the cell cycle and enter a 'dormant' developmental state that mimics diapause following MYC depletion (Scognamiglio et al, 2016). This is likely to be related to the ability of MYC to control CDK activity and is an interesting example of how proliferation and developmental status are coupled.…”

OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors

“…Depletion of MYC in tissue culture or deletion of MYC or MAX genes during mouse development shows that MYC/MAX complexes have essential functions during embryonic development and are necessary for growth of multiple cell types in vivo and in culture [4][5][6] . This correlates with the observation that multiple target genes of MYC encode proteins involved in basic cellular processes, including protein translation, cell cycle progression, DNA synthesis and intermediary metabolism 1 .…”