MYC-DRIVEN EPIGENETIC MEMORY MAINTAINS EMBRYONIC STEM CELL IDENTITY

Stem cells balance their self-renewal and differentiation potential by integrating environmental signals with the Transcriptional Regulatory Network (TRN). Moreover, the integration between extrinsic and intrinsic signals affects the maintenance of their epigenetic state, establishing an accurate cells identity. Although c-Myc transcription factors plays a major role in stem cells self-renewal and pluripotency, their mechanisms of actions and their ability to establish an epigenetic memory remains poorly defined. We addressed this point by profiling the epigenetic pattern and gene expression in Embryonic Stem (ES) cells, whose growth depends on conditional c-Myc activity. Here we show that c-Myc potentiates the Wnt/β- Catenin signaling pathway, which cooperates with the transcriptional regulatory network in sustaining ES cells self-renewal. c-Myc activation results in the transcriptional repression of Wnt antagonists Dkk1 and Sfrp1 through the direct recruitment of PRC2 on these targets. We found that, through these molecular mechanisms, c-Myc promotes pluripotency and self-renewal of ES cells by activating an alternative epigenetic program. Finally our data suggest that the consequent potentiation of the autocrine Wnt/β-Catenin signaling induces the transcriptional activation of the endogenous Myc family members, which in turn activates a Myc-driven self-reinforcing circuit. Thus, our data unravel a Myc-dependent selfpropagating epigenetic memory in the maintenance of ES cell identity.