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Cell Stem Cell. 2019 May 2;24(5):785-801.e7. doi: 10.1016/j.stem.2019.03.017. Epub 2019 Apr 25.

Complementary Activity of ETV5, RBPJ, and TCF3 Drives Formative Transition from Naive Pluripotency.

Author information

1
Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK. Electronic address: tuzer.kalkan@gmail.com.
2
Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK.
3
Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK.
4
Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.
5
Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK; Department of Molecular Biology, Faculty of Science, Radboud University, 6525GA Nijmegen, the Netherlands.
6
Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK; Department of Molecular Biology, Faculty of Science, Radboud University, 6525GA Nijmegen, the Netherlands. Electronic address: austin.smith@cscr.cam.ac.uk.

Abstract

The gene regulatory network (GRN) of naive mouse embryonic stem cells (ESCs) must be reconfigured to enable lineage commitment. TCF3 sanctions rewiring by suppressing components of the ESC transcription factor circuitry. However, TCF3 depletion only delays and does not prevent transition to formative pluripotency. Here, we delineate additional contributions of the ETS-family transcription factor ETV5 and the repressor RBPJ. In response to ERK signaling, ETV5 switches activity from supporting self-renewal and undergoes genome relocation linked to commissioning of enhancers activated in formative epiblast. Independent upregulation of RBPJ prevents re-expression of potent naive factors, TBX3 and NANOG, to secure exit from the naive state. Triple deletion of Etv5, Rbpj, and Tcf3 disables ESCs, such that they remain largely undifferentiated and locked in self-renewal, even in the presence of differentiation stimuli. Thus, genetic elimination of three complementary drivers of network transition stalls developmental progression, emulating environmental insulation by small-molecule inhibitors.

KEYWORDS:

ETS factors; RBPJ; commitment; differentiation; embryonic stem cell; epiblast; gene regulatory network; pluripotency; self-renewal

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