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Cell. 2016 Feb 11;164(4):668-80. doi: 10.1016/j.cell.2015.12.033.

Myc Depletion Induces a Pluripotent Dormant State Mimicking Diapause.

Author information

1
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.
2
Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.
3
Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
4
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.
5
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
6
Welcome Trust-Medical Research Council Stem Cell Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
7
Stem Cell and Regenerative Medicine Group, Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Koellikerstraße 6, 97070 Würzburg, Germany.
8
Transgenic Service, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
9
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
10
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.
11
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.
12
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.

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.

PMID:
26871632
PMCID:
PMC4752822
DOI:
10.1016/j.cell.2015.12.033
[Indexed for MEDLINE]
Free PMC Article

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