Myc-driven self-reinforcing regulatory network maintains Embryonic Stem cell identity

15th May 2015
Versione stampabile

Venue: Edificio Povo 2, via Sommarive nr. 9, Povo (Tn) - Room B104
 at 11:00 a.m.

  • Alessio Zippo -  Fondazione Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi”, Milan Italy

Stem Stem cell self renew and cell lineages commitment are followed by dynamic changes in the chromatin state, which then ensure the maintenance of cell identity through multiple rounds of cell divisions. Albeit of importance, the molecular mechanisms governing the transition from a temporary to a stable and heritable gene expression program in the absence of the instructive signals, are largely undefined.  We asked whether Myc, which plays a central role in ESCs self renew and pluripotency, represents a critical hub bridging environmental signals with the transcriptional regulatory network (TRN). We addressed this point by profiling epigenetic pattern and gene expression in ESCs whose growth depends on conditional Myc activity. Here we report the central role of Myc in establishing an epigenetic memory in ESCs by sustaining the self-reinforcing TRN via the potentiation of the Wnt/β-catenin pathway and the inhibition of the autocrine Fgf4/Erk pathway, thus recapitulating the ground state of ESCs. We show that the activation of MycER establishes a positive feedback loop by repressing the Wnt antagonists via an increased loading of PRC2 and consequently an accumulation of H3K27me3 on these targets. The resulting potentiation of autocrine Wnt/β-catenin signaling induces transcriptional activation of the endogenous Myc family members, which in turns activates a Myc-driven self-reinforcing circuit. Thus, our data unravel a Myc-dependent self-propagating epigenetic memory, which plays a major role in the maintenance of ESC self-renewal capacity.