A Myc-driven self-reinforcing regulatory network maintains mouse embryonic stem cell identity

• DOI: 10.1038/ncomms11903
• Publication Date: 2016-06-15T17:15:29Z
• Authors: Luca Fagnocchi; Alessandro Cherubini; Hiroshi Hatsuda; Alessandra Fasciani; Stefania Mazzoleni; Vittoria Poli; Valeria Berno; Riccardo L. Rossi; Rolland Reinbold; Max Endele; Timm Schroeder; Marina Rocchigiani; Żaneta Szkarłat; Salvatore Oliviero; Stephen Dalton; Alessio Zippo
• Keywords: Feedback, Physiological; 0303 health sciences; Stem cell; Transcription, Genetic; Science; Q; Polycomb-Group Proteins; Mouse Embryonic Stem Cells; Leukemia Inhibitory Factor; Article; Epigenesis, Genetic; Proto-Oncogene Proteins c-myc; Mice; 03 medical and health sciences; Biochemistry, Genetics and Molecular Biology (all); Chemistry (all); Physics and Astronomy (all); Animals; Gene Regulatory Networks; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all); Cell Self Renewal; Wnt Signaling Pathway

AbstractStem cell identity depends on the integration of extrinsic and intrinsic signals, which directly influence the maintenance of their epigenetic state. Although Myc transcription factors play a major role in stem cell self-renewal and pluripotency, their integration with signalling pathways and epigenetic regulators remains poorly defined. We addressed this point by profiling the gene expression and epigenetic pattern in ESCs whose growth depends on conditional Myc activity. Here we show that Myc potentiates the Wnt/β-catenin signalling pathway, which cooperates with the transcriptional regulatory network in sustaining ESC self-renewal. Myc activation results in the transcriptional repression of Wnt antagonists through the direct recruitment of PRC2 on these targets. The consequent potentiation of the autocrine Wnt/β-catenin signalling 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 self-propagating epigenetic memory in the maintenance of ESC self-renewal capacity.