A Myc-driven self-reinforcing regulatory network maintains mouse embryonic stem cell identity.
Stem 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.
Department of Epigenetics, Fondazione Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Via Francesco Sforza 35, Milan 20122, Italy.
Luca
L
Fagnocchi
Department of Epigenetics, Fondazione Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Via Francesco Sforza 35, Milan 20122, Italy.
Alessandro
A
Cherubini
Department of Epigenetics, Fondazione Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Via Francesco Sforza 35, Milan 20122, Italy.
Hiroshi
H
Hatsuda
Department of Epigenetics, Fondazione Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Via Francesco Sforza 35, Milan 20122, Italy.
Alessandra
A
Fasciani
Department of Epigenetics, Fondazione Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Via Francesco Sforza 35, Milan 20122, Italy.
Stefania
S
Mazzoleni
Department of Epigenetics, Fondazione Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Via Francesco Sforza 35, Milan 20122, Italy.
Vittoria
V
Poli
Department of Epigenetics, Fondazione Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Via Francesco Sforza 35, Milan 20122, Italy.
Valeria
V
Berno
Department of Epigenetics, Fondazione Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Via Francesco Sforza 35, Milan 20122, Italy.
Riccardo L
RL
Rossi
Institute of Biomedical Technologies, National Research Council, via Cervi 93, Segrate-Milan 20090, Italy.
Rolland
R
Reinbold
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, Basel 4058, Switzerland.
Max
M
Endele
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, Basel 4058, Switzerland.
Timm
T
Schroeder
Dipartimento di Biotecnologie, Chimica e Farmacia Università di Siena, Via Fiorentina 1, Siena 53100, Italy.|Human Genetic Foundation (HuGeF), via Nizza 52, Torino 10126, Italy.
Marina
M
Rocchigiani
Dipartimento di Biotecnologie, Chimica e Farmacia Università di Siena, Via Fiorentina 1, Siena 53100, Italy.|Human Genetic Foundation (HuGeF), via Nizza 52, Torino 10126, Italy.
Żaneta
Ż
Szkarłat
Dipartimento di Biotecnologie, Chimica e Farmacia Università di Siena, Via Fiorentina 1, Siena 53100, Italy.|Human Genetic Foundation (HuGeF), via Nizza 52, Torino 10126, Italy.
Salvatore
S
Oliviero
Department of Biochemistry and Molecular Biology, University of Georgia, 500 D.W. Brooks Drive, Athens, Georgia 30602, USA.
Stephen
S
Dalton
Department of Epigenetics, Fondazione Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Via Francesco Sforza 35, Milan 20122, Italy.
Alessio
A
Zippo
D000818:Animals; D000066673:Cell Self Renewal / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D025461:Feedback, Physiological / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics*; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D063146:Polycomb-Group Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics
D053605:Leukemia Inhibitory Factor; D063146:Polycomb-Group Proteins; D016271:Proto-Oncogene Proteins c-myc