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Cell Rep. 2016 Jun 21;15(12):2651-64. doi: 10.1016/j.celrep.2016.05.041. Epub 2016 Jun 9.

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.

Author information

1
Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," CNR, Via P. Castellino 111, 80131 Naples, Italy; IRCCS Neuromed, 86077 Pozzilli (IS), Italy.
2
Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," CNR, Via P. Castellino 111, 80131 Naples, Italy.
3
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via Sergio Pansini 5, 80131 Naples, Italy.
4
Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, Via L. De Crecchio, 7, 80138 Naples, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei, 34, 80087 Pozzuoli (NA), Italy.
5
Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," CNR, Via P. Castellino 111, 80131 Naples, Italy; IRCCS Neuromed, 86077 Pozzilli (IS), Italy. Electronic address: antonio.simeone@igb.cnr.it.

Abstract

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:

Nanog; Otx2; embryonic stem cells; pluripotency; preimplantation epiblast

PMID:
27292645
DOI:
10.1016/j.celrep.2016.05.041
[Indexed for MEDLINE]
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