Figure 3.

MYC induces and epigenetic memory mechanism in ESCs. (A) Mouse ESCs can be maintained upon LIF withdrawal, providing activation of MYC-ER, which leads to WNT pathway reinforcement, through PRC2-mediated repression of its antagonist, and induction of endogenous MYC and MYCN. If MYC-ER remains activate for short term (e.g., 3–6 days), mESCs differentiate spontaneously once it is inactivated. On the contrary, long term activation of MYC-ER (at least 12 days) leads to the stabilization of WNT reinforcement and concomitant induction of MYC/MYCN, even in the absence of the original stimulus (OHT), thanks to a self-reinforcing loop. This epigenetic memory mechanism permits the maintenance of MYC-derived mESCs in absence of both LIF and MYC-ER activation (Fagnocchi et al., 2016a). (B) The epigenetic memory of MYC-derived mESCs permits their reversion to a LIF-dependent state of pluripotency. LIF/serum maintained mESCs are dependent on LIF/JAK/STAT cascade; hence LIF withdrawal leads to their differentiation. On the contrary, inhibition of both PRC2 activity and WNT pathway do not affect their pluripotent state. Both MYC-dependent and MYC-derived mESCs are, instead, insensitive to LIF withdrawal, but rather strictly dependent on the MYC/PRC2-mediated activation of WNT pathway. Importantly, culturing MYC-derived mESCs in LIF/serum medium reverts them back to a LIF-dependent but PRC2/WNT-independent pluripotent state, underlying the epigenetic nature of the memory mechanism which permits their derivation. Accordingly, the expression of downstream targets of both LIF and WNT pathways (SOCS3 and FZD7) is epigenetically controlled and switched between the different pluripotent states described (Fagnocchi et al., 2016a). Solid green and red arrows indicate high or low expression on nearby genes/functions, respectively.