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Cell Stem Cell. 2016 Jan 7;18(1):118-33. doi: 10.1016/j.stem.2015.09.010.

Foxd3 Promotes Exit from Naive Pluripotency through Enhancer Decommissioning and Inhibits Germline Specification.

Author information

1
Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany.
2
The Chemical Proteomics Center and State Key Laboratory of Drug Research, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
3
Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.
4
Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
5
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany. Electronic address: aradaigl@uni-koeln.de.

Abstract

Following implantation, mouse epiblast cells transit from a naive to a primed state in which they are competent for both somatic and primordial germ cell (PGC) specification. Using mouse embryonic stem cells as an in vitro model to study the transcriptional regulatory principles orchestrating peri-implantation development, here we show that the transcription factor Foxd3 is necessary for exit from naive pluripotency and progression to a primed pluripotent state. During this transition, Foxd3 acts as a repressor that dismantles a significant fraction of the naive pluripotency expression program through decommissioning of active enhancers associated with key naive pluripotency and early germline genes. Subsequently, Foxd3 needs to be silenced in primed pluripotent cells to allow re-activation of relevant genes required for proper PGC specification. Our findings therefore uncover a cycle of activation and deactivation of Foxd3 required for exit from naive pluripotency and subsequent PGC specification.

PMID:
26748758
PMCID:
PMC5048917
DOI:
10.1016/j.stem.2015.09.010
[Indexed for MEDLINE]
Free PMC Article

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