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.
Bibliographical noteFunding Information:
We thank F. Lohmann for advice on the ChIP assay, J. Bieker (Mount Sinai School of Medicine) and G. Blobel (University of Pennsylvania) for critical reading of the manuscript, I. George and M. Grisotto for cell sorting, and the Flow Cytometry Shared Research Facility of Mount Sinai School of Medicine. This work was supported in part by a National Institutes of Health grant RO1 DK077174, an American Cancer Society Research Scholarship (RSG LIB-110480), a Career Enhancement Award (K18 HL76510-01), a Black Family Stem Cell Institute Exploratory Research Award, a New York State Stem Cell Science (NYSTEM) award (CO24408), an Irma Hirschl/Weill-Caulier Trust Research Award and a Roche Foundation for Anemia Research (RoFAR) Award to S.G., and an NIH P20 GM75019 (S.G. CoPI).
All Science Journal Classification (ASJC) codes
- Cell Biology