Functional Antagonism between OTX2 and NANOG Specifies a Spectrum of Heterogeneous Identities in Embryonic Stem Cells

Dario Acampora, Luca Giovanni Di Giovannantonio, Arcomaria Garofalo, Vincenzo Nigro, Daniela Omodei, Alessia Lombardi, Jingchao Zhang, Ian Chambers, Antonio Simeone

Research output: Contribution to journalArticle

Abstract

Embryonic stem cells (ESCs) cultured in leukemia inhibitory factor (LIF) plus fetal bovine serum (FBS) exhibit heterogeneity in the expression of naive and primed transcription factors. This heterogeneity reflects the dynamic condition of ESCs and their versatility to promptly respond to signaling effectors promoting naive or primed pluripotency. Here, we report that ESCs lacking Nanog or overexpressing Otx2 exhibit an early primed identity in LIF + FBS and fail to convert into 2i-induced naive state. Conversely, Otx2-null ESCs possess naive identity features in LIF + FBS similar to Nanog-overexpressing ESCs and convert poorly into FGF-induced early primed state. When both Nanog and Otx2 are inactivated, ESCs cultured in LIF + FBS exhibit primed identity and weakened ability to convert into naive state. These data suggest that, through mutual antagonism, NANOG and OTX2 specify the heterogeneous identity of ESCs cultured in LIF + FBS and individually predispose them for optimal response to naive or primed inducing factors. In this article, Simeone and colleagues study the molecular mechanism controlling the heterogeneous and flexible identity of ESCs cultured in LIF + FBS. They analyze a series of ESC lines carrying different dosages of OTX2 and/or NANOG. They find that synergism between the OTX2 and NANOG antagonistic regulatory networks specifies the identity of ESCs in LIF + FBS.

Original languageEnglish
Pages (from-to)1642-1659
Number of pages18
JournalStem Cell Reports
Volume9
Issue number5
DOIs
Publication statusPublished - Nov 14 2017

Keywords

  • embryonic stem cell heterogeneity
  • LIF signaling
  • NANOG
  • OTX2
  • pluripotency

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Acampora, D., Di Giovannantonio, L. G., Garofalo, A., Nigro, V., Omodei, D., Lombardi, A., Zhang, J., Chambers, I., & Simeone, A. (2017). Functional Antagonism between OTX2 and NANOG Specifies a Spectrum of Heterogeneous Identities in Embryonic Stem Cells. Stem Cell Reports, 9(5), 1642-1659. https://doi.org/10.1016/j.stemcr.2017.09.019