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
Dario Acampora,
Daniela Omodei,
Giuseppe Petrosino,
Arcomaria Garofalo,
Marco Savarese,
Vincenzo Nigro,
Luca Giovanni Di Giovannantonio,
Vincenzo Mercadante,
Antonio Simeone
Affiliations
Dario Acampora
Institute of Genetics and Biophysics “Adriano Buzzati-Traverso,” CNR, Via P. Castellino 111, 80131 Naples, Italy
Daniela Omodei
Institute of Genetics and Biophysics “Adriano Buzzati-Traverso,” CNR, Via P. Castellino 111, 80131 Naples, Italy
Giuseppe Petrosino
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via Sergio Pansini 5, 80131 Naples, Italy
Arcomaria Garofalo
Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, Via L. De Crecchio, 7, 80138 Naples, Italy
Marco Savarese
Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, Via L. De Crecchio, 7, 80138 Naples, Italy
Vincenzo Nigro
Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, Via L. De Crecchio, 7, 80138 Naples, Italy
Luca Giovanni Di Giovannantonio
Institute of Genetics and Biophysics “Adriano Buzzati-Traverso,” CNR, Via P. Castellino 111, 80131 Naples, Italy
Vincenzo Mercadante
Institute of Genetics and Biophysics “Adriano Buzzati-Traverso,” CNR, Via P. Castellino 111, 80131 Naples, Italy
Antonio Simeone
Institute of Genetics and Biophysics “Adriano Buzzati-Traverso,” CNR, Via P. Castellino 111, 80131 Naples, Italy
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.
