title: Myc Depletion Induces a Pluripotent Dormant State Mimicking Diapause.
abstract: Mouse embryonic stem cells (ESCs) are maintained in a naive ground state of pluripotency in the presence of MEK and GSK3 inhibitors. Here, we show that ground-state ESCs express low Myc levels. Deletion of both c-myc and N-myc (dKO) or pharmacological inhibition of Myc activity strongly decreases transcription, splicing, and protein synthesis, leading to proliferation arrest. This process is reversible and occurs without affecting pluripotency, suggesting that Myc-depleted stem cells enter a state of dormancy similar to embryonic diapause. Indeed, c-Myc is depleted in diapaused blastocysts, and the differential expression signatures of dKO ESCs and diapaused epiblasts are remarkably similar. Following Myc inhibition, pre-implantation blastocysts enter biosynthetic dormancy but can progress through their normal developmental program after transfer into pseudo-pregnant recipients. Our study shows that Myc controls the biosynthetic machinery of stem cells without affecting their potency, thus regulating their entry and exit from the dormant state.
authors.affiliation: Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Roberta
authors.initials: R
authors.lastname: Scognamiglio
authors.affiliation: Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Cabezas-Wallscheid
authors.affiliation: Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Marc Christian
authors.initials: MC
authors.lastname: Thier
authors.affiliation: Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.
authors.forename: Sandro
authors.initials: S
authors.lastname: Altamura
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Reyes
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Hematopoietic Stem Cells and Stress Group, Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Áine M
authors.initials: ÁM
authors.lastname: Prendergast
authors.affiliation: Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baumgärtner
authors.affiliation: Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Larissa S
authors.initials: LS
authors.lastname: Carnevalli
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Ann
authors.initials: A
authors.lastname: Atzberger
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Hematopoietic Stem Cells and Stress Group, Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Haas
authors.affiliation: Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: von Paleske
authors.affiliation: Welcome Trust-Medical Research Council Stem Cell Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Boroviak
authors.affiliation: Stem Cell and Regenerative Medicine Group, Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Koellikerstraße 6, 97070 Würzburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Wörsdörfer
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Hematopoietic Stem Cells and Stress Group, Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Marieke A G
authors.initials: MA
authors.lastname: Essers
authors.affiliation: Transgenic Service, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kloz
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Eisenman
authors.affiliation: Stem Cell and Regenerative Medicine Group, Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Koellikerstraße 6, 97070 Würzburg, Germany; Institute of Molecular Biology, Department of Genomics, Stem Cell Biology & Regenerative Medicine, Leopold-Franzens-Universität Innsbruck, Technikerstraße 25, 6020 Innsbruck, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Edenhofer
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany; Welcome Trust-Medical Research Council Stem Cell Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Bertone
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Huber
authors.affiliation: Transgenic Service, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Franciscus
authors.initials: F
authors.lastname: van der Hoeven
authors.affiliation: Welcome Trust-Medical Research Council Stem Cell Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Austin
authors.initials: A
authors.lastname: Smith
authors.affiliation: Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. Electronic address: a.trumpp@dkfz.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D016259:Genes, myc; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*
chemical_list: C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc