title: FOXO1 is an essential regulator of pluripotency in human embryonic stem cells.
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. 4), NANOG (refs 5, 6), SOX2 (ref. 7) 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.
authors.affiliation: Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Safak
authors.initials: S
authors.lastname: Yalcin
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Tsung-Yin J
authors.initials: TY
authors.lastname: Yeh
authors.forename: Seung-Min
authors.initials: SM
authors.lastname: Lee
authors.forename: Jie
authors.initials: J
authors.lastname: Su
authors.forename: Sathish Kumar
authors.initials: SK
authors.lastname: Mungamuri
authors.forename: Pauline
authors.initials: P
authors.lastname: Rimmelé
authors.forename: Marion
authors.initials: M
authors.lastname: Kennedy
authors.forename: Rani
authors.initials: R
authors.lastname: Sellers
authors.forename: Markus
authors.initials: M
authors.lastname: Landthaler
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
authors.forename: Nai-Wen
authors.initials: NW
authors.lastname: Chi
authors.forename: Ihor
authors.initials: I
authors.lastname: Lemischka
authors.forename: Gordon
authors.initials: G
authors.lastname: Keller
authors.forename: Saghi
authors.initials: S
authors.lastname: Ghaffari
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation; D004318:Doxycycline / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D010766:Phosphorylation; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D017382:Reactive Oxygen Species; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D004318:Doxycycline