FOXO1 is an Essential Regulator of Pluripotency in Human Embryonic Stem Cells

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2011 Aug 2

PMID 21804543

Citations 151

Authors

Xin Zhang

Safak Yalcin

Dung-Fang Lee

Tsung-Yin J Yeh

Seung-Min Lee

Jie Su

Sathish Kumar Mungamuri

Pauline Rimmele

Marion Kennedy

Rani Sellers

Markus Landthaler

Thomas Tuschl

Nai-Wen Chi

Ihor Lemischka

Gordon Keller

Saghi Ghaffari

Affiliations

Soon will be listed here.

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.

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References

Boyer L, Mathur D, Jaenisch R . Molecular control of pluripotency. Curr Opin Genet Dev. 2006; 16(5):455-62. DOI: 10.1016/j.gde.2006.08.009. View

Renault V, Rafalski V, Morgan A, Salih D, Brett J, Webb A . FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell. 2009; 5(5):527-39. PMC: 2775802. DOI: 10.1016/j.stem.2009.09.014. View

Brunet A, Bonni A, Zigmond M, Lin M, Juo P, Hu L . Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999; 96(6):857-68. DOI: 10.1016/s0092-8674(00)80595-4. View

van den Berg M, Burgering B . Integrating opposing signals toward Forkhead box O. Antioxid Redox Signal. 2010; 14(4):607-21. DOI: 10.1089/ars.2010.3415. View

Castrillon D, Miao L, Kollipara R, Horner J, DePinho R . Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science. 2003; 301(5630):215-8. DOI: 10.1126/science.1086336. View

Mahmud D, Deb D, Platanias L, Uddin S, Wickrema A . Phosphorylation of forkhead transcription factors by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells. Oncogene. 2002; 21(10):1556-62. DOI: 10.1038/sj.onc.1205230. View

Lohmann F, Bieker J . Activation of Eklf expression during hematopoiesis by Gata2 and Smad5 prior to erythroid commitment. Development. 2008; 135(12):2071-82. DOI: 10.1242/dev.018200. View

Niwa H . How is pluripotency determined and maintained?. Development. 2007; 134(4):635-46. DOI: 10.1242/dev.02787. View

Yamagata K, Daitoku H, Takahashi Y, Namiki K, Hisatake K, Kako K . Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol Cell. 2008; 32(2):221-31. DOI: 10.1016/j.molcel.2008.09.013. View

10.

Adewumi O, Aflatoonian B, Ahrlund-Richter L, Amit M, Andrews P, Beighton G . Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nat Biotechnol. 2007; 25(7):803-16. DOI: 10.1038/nbt1318. View

11.

Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y . TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010; 463(7281):676-80. DOI: 10.1038/nature08734. View

12.

Hu M, Lee D, Xia W, Golfman L, Ou-Yang F, Yang J . IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004; 117(2):225-37. DOI: 10.1016/s0092-8674(04)00302-2. View

13.

Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk G . Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. Nat Biotechnol. 2004; 22(6):707-16. DOI: 10.1038/nbt971. View

14.

Paik J, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z . FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell. 2007; 128(2):309-23. PMC: 1855089. DOI: 10.1016/j.cell.2006.12.029. View

15.

Jaenisch R, Young R . Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell. 2008; 132(4):567-82. PMC: 4142810. DOI: 10.1016/j.cell.2008.01.015. View

16.

Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M . Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A. 2004; 101(27):10042-7. PMC: 454161. DOI: 10.1073/pnas.0400593101. View

17.

Brunet A, Sweeney L, Sturgill J, Chua K, Greer P, Lin Y . Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004; 303(5666):2011-5. DOI: 10.1126/science.1094637. View

18.

Im H, Grass J, Johnson K, Boyer M, Wu J, Bresnick E . Measurement of protein-DNA interactions in vivo by chromatin immunoprecipitation. Methods Mol Biol. 2004; 284:129-46. DOI: 10.1385/1-59259-816-1:129. View

19.

Jiang J, Chan Y, Loh Y, Cai J, Tong G, Lim C . A core Klf circuitry regulates self-renewal of embryonic stem cells. Nat Cell Biol. 2008; 10(3):353-60. DOI: 10.1038/ncb1698. View

20.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View