Cell Reports
Volume 15, Issue 12, 21 June 2016, Pages 2651-2664
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Article
Loss of the Otx2-Binding Site in the Nanog Promoter Affects the Integrity of Embryonic Stem Cell Subtypes and Specification of Inner Cell Mass-Derived Epiblast

https://doi.org/10.1016/j.celrep.2016.05.041Get rights and content
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Highlights

  • Otx2 binds to the promoter/enhancer region of Oct4, Sox2, and Nanog in ESCs and EpiSCs

  • Otx2 binding to the Nanog promoter helps maintain the integrity of ESC compartments

  • Loss of this Otx2-binding site induces primed-like features in ESCs

  • Otx2 regulation of Nanog contributes to ICM differentiation of the epiblast

Summary

Mouse embryonic stem cells (ESCs) and the inner cell mass (ICM)-derived epiblast exhibit naive pluripotency. ESC-derived epiblast stem cells (EpiSCs) and the postimplantation epiblast exhibit primed pluripotency. Although core pluripotency factors are well-characterized, additional regulators, including Otx2, recently have been shown to function during the transition from naive to primed pluripotency. Here we uncover a role for Otx2 in the control of the naive pluripotent state. We analyzed Otx2-binding activity in ESCs and EpiSCs and identified Nanog, Oct4, and Sox2 as direct targets. To unravel the Otx2 transcriptional network, we targeted the strongest Otx2-binding site in the Nanog promoter, finding that this site modulates the size of specific ESC-subtype compartments in cultured cells and promotes Nanog expression in vivo, predisposing ICM differentiation to epiblast. Otx2-mediated Nanog regulation thus contributes to the integrity of the ESC state and cell lineage specification in preimplantation development.

Keywords

Otx2
Nanog
pluripotency
embryonic stem cells
preimplantation epiblast

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