FOXO1 is an essential regulator of pluripotency in human embryonic stem cells

Xin Zhang, Safak Yalcin, Dung Fang Lee, Tsung Yin J. Yeh, Seung Min Lee, Jie Su, Sathish Kumar Mungamuri, Pauline Rimmelé, Marion Kennedy, Rani Sellers, Markus Landthaler, Thomas Tuschl, Nai Wen Chi, Ihor Lemischka, Gordon Keller, Saghi Ghaffari

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141 Scopus citations

Abstract

Pluripotency of embryonic stem cells (ESCs) is defined by their ability to differentiate into three germ layers and derivative cell types and is established by an interactive network of proteins including OCT4 (also known as POU5F1; ref.), NANOG (refs,), SOX2 (ref.) and their binding partners. The forkhead box O (FoxO) transcription factors are evolutionarily conserved regulators of longevity and stress response whose function is inhibited by AKT protein kinase. FoxO proteins are required for the maintenance of somatic and cancer stem cells; however, their function in ESCs is unknown. We show that FOXO1 is essential for the maintenance of human ESC pluripotency, and that an orthologue of FOXO1 (Foxo1) exerts a similar function in mouse ESCs. This function is probably mediated through direct control by FOXO1 of OCT4 and SOX2 gene expression through occupation and activation of their respective promoters. Finally, AKT is not the predominant regulator of FOXO1 in human ESCs. Together these results indicate that FOXO1 is a component of the circuitry of human ESC pluripotency. These findings have critical implications for stem cell biology, development, longevity and reprogramming, with potentially important ramifications for therapy.

Original languageEnglish (US)
Pages (from-to)1092-1101
Number of pages10
JournalNature Cell Biology
Volume13
Issue number9
DOIs
StatePublished - Sep 1 2011

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Zhang, X., Yalcin, S., Lee, D. F., Yeh, T. Y. J., Lee, S. M., Su, J., Mungamuri, S. K., Rimmelé, P., Kennedy, M., Sellers, R., Landthaler, M., Tuschl, T., Chi, N. W., Lemischka, I., Keller, G., & Ghaffari, S. (2011). FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nature Cell Biology, 13(9), 1092-1101. https://doi.org/10.1038/ncb2293