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

doi:10.1038/ncb2293

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

Department of Food and Nutrition

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155 Citations (Scopus)

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 language	English
Pages (from-to)	1092-1101
Number of pages	10
Journal	Nature Cell Biology
Volume	13
Issue number	9
DOIs	https://doi.org/10.1038/ncb2293
Publication status	Published - 2011 Sep

Bibliographical note

Funding 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).

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Cell Biology

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Zhang, Xin ; Yalcin, Safak ; Lee, Dung Fang ; Yeh, Tsung Yin J. ; Lee, Seung Min ; Su, Jie ; Mungamuri, Sathish Kumar ; Rimmelé, Pauline ; Kennedy, Marion ; Sellers, Rani ; Landthaler, Markus ; Tuschl, Thomas ; Chi, Nai Wen ; Lemischka, Ihor ; Keller, Gordon ; Ghaffari, Saghi. / FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. In: Nature Cell Biology. 2011 ; Vol. 13, No. 9. pp. 1092-1101.

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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.), 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.",

author = "Xin Zhang and Safak Yalcin and Lee, {Dung Fang} and Yeh, {Tsung Yin J.} and Lee, {Seung Min} and Jie Su and Mungamuri, {Sathish Kumar} and Pauline Rimmel{\'e} and Marion Kennedy and Rani Sellers and Markus Landthaler and Thomas Tuschl and Chi, {Nai Wen} and Ihor Lemischka and Gordon Keller and Saghi Ghaffari",

note = "Funding 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).",

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FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. / Zhang, Xin; Yalcin, Safak; Lee, Dung Fang; Yeh, Tsung Yin J.; Lee, Seung Min; Su, Jie; Mungamuri, Sathish Kumar; Rimmelé, Pauline; Kennedy, Marion; Sellers, Rani; Landthaler, Markus; Tuschl, Thomas; Chi, Nai Wen; Lemischka, Ihor; Keller, Gordon; Ghaffari, Saghi.

In: Nature Cell Biology, Vol. 13, No. 9, 09.2011, p. 1092-1101.

Research output: Contribution to journal › Article › peer-review

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AU - Zhang, Xin

AU - Yalcin, Safak

AU - Lee, Dung Fang

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AU - Lee, Seung Min

AU - Su, Jie

AU - Mungamuri, Sathish Kumar

AU - Rimmelé, Pauline

AU - Kennedy, Marion

AU - Sellers, Rani

AU - Landthaler, Markus

AU - Tuschl, Thomas

AU - Chi, Nai Wen

AU - Lemischka, Ihor

AU - Keller, Gordon

AU - Ghaffari, Saghi

N1 - Funding 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).

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N2 - 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.

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

Abstract

Bibliographical note

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