TET2 Deficiency Inhibits Mesoderm and Hematopoietic Differentiation in Human Embryonic Stem Cells

Authors

  • Thierry Langlois,

    1. Institut National de la Santé et de la Recherche Médicale, UMR 1009, Laboratory of Excellence GR-Ex, 114 rue Edouard Vaillant, Villejuif, Paris, France
    2. Institut Gustave Roussy, Villejuif, Paris, France
    3. Université Paris Sud 11, Orsay, France
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  • Barbara da Costa Reis Monte-Mor,

    1. Institut National de la Santé et de la Recherche Médicale, UMR 1009, Laboratory of Excellence GR-Ex, 114 rue Edouard Vaillant, Villejuif, Paris, France
    2. Institut Gustave Roussy, Villejuif, Paris, France
    3. Université Paris Sud 11, Orsay, France
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  • Gaëlle Lenglet,

    1. Institut National de la Santé et de la Recherche Médicale, UMR 1009, Laboratory of Excellence GR-Ex, 114 rue Edouard Vaillant, Villejuif, Paris, France
    2. Institut Gustave Roussy, Villejuif, Paris, France
    3. Université Paris Sud 11, Orsay, France
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  • Nathalie Droin,

    1. Institut National de la Santé et de la Recherche Médicale, UMR 1009, Laboratory of Excellence GR-Ex, 114 rue Edouard Vaillant, Villejuif, Paris, France
    2. Institut Gustave Roussy, Villejuif, Paris, France
    3. Université Paris Sud 11, Orsay, France
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  • Caroline Marty,

    1. Institut National de la Santé et de la Recherche Médicale, UMR 1009, Laboratory of Excellence GR-Ex, 114 rue Edouard Vaillant, Villejuif, Paris, France
    2. Institut Gustave Roussy, Villejuif, Paris, France
    3. Université Paris Sud 11, Orsay, France
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  • Jean-Pierre Le Couédic,

    1. Institut National de la Santé et de la Recherche Médicale, UMR 1009, Laboratory of Excellence GR-Ex, 114 rue Edouard Vaillant, Villejuif, Paris, France
    2. Institut Gustave Roussy, Villejuif, Paris, France
    3. Université Paris Sud 11, Orsay, France
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  • Carole Almire,

    1. Institut National de la Santé et de la Recherche Médicale, UMR 1009, Laboratory of Excellence GR-Ex, 114 rue Edouard Vaillant, Villejuif, Paris, France
    2. Université Paris Sud 11, Orsay, France
    3. Université Paris 6 Pierre et Marie Curie, France
    4. Assistance Publique—Hôpitaux de Paris, Laboratoire d'Hématologie, Hôpital Saint-Antoine, Paris, France
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  • Nathalie Auger,

    1. Institut Gustave Roussy, Villejuif, Paris, France
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  • Thomas Mercher,

    1. Institut National de la Santé et de la Recherche Médicale U985, France
    2. Institut Gustave Roussy, Villejuif, Paris, France
    3. Université Paris Sud 11, Orsay, France
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  • François Delhommeau,

    1. Institut National de la Santé et de la Recherche Médicale, UMR 1009, Laboratory of Excellence GR-Ex, 114 rue Edouard Vaillant, Villejuif, Paris, France
    2. Université Paris Sud 11, Orsay, France
    3. Université Paris 6 Pierre et Marie Curie, France
    4. Assistance Publique—Hôpitaux de Paris, Laboratoire d'Hématologie, Hôpital Saint-Antoine, Paris, France
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  • Jesper Christensen,

    1. Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen N, Denmark
    2. Centre for Epigenetics, University of Copenhagen, Copenhagen N, Denmark
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  • Kristian Helin,

    1. Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen N, Denmark
    2. Centre for Epigenetics, University of Copenhagen, Copenhagen N, Denmark
    3. The Danish Stem Cell Center (Danstem), University of Copenhagen, Copenhagen N, Denmark
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  • Najet Debili,

    1. Institut National de la Santé et de la Recherche Médicale, UMR 1009, Laboratory of Excellence GR-Ex, 114 rue Edouard Vaillant, Villejuif, Paris, France
    2. Institut Gustave Roussy, Villejuif, Paris, France
    3. Université Paris Sud 11, Orsay, France
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  • François Fuks,

    1. Laboratory of Cancer Epigenetics, Free University of Brussels (U.L.B.), Faculty of Medicine, Brussels, Belgium
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  • Olivier A. Bernard,

    1. Institut National de la Santé et de la Recherche Médicale U985, France
    2. Institut Gustave Roussy, Villejuif, Paris, France
    3. Université Paris Sud 11, Orsay, France
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  • Eric Solary,

    1. Institut National de la Santé et de la Recherche Médicale, UMR 1009, Laboratory of Excellence GR-Ex, 114 rue Edouard Vaillant, Villejuif, Paris, France
    2. Institut Gustave Roussy, Villejuif, Paris, France
    3. Université Paris Sud 11, Orsay, France
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  • William Vainchenker,

    Corresponding author
    1. Institut National de la Santé et de la Recherche Médicale, UMR 1009, Laboratory of Excellence GR-Ex, 114 rue Edouard Vaillant, Villejuif, Paris, France
    2. Institut Gustave Roussy, Villejuif, Paris, France
    3. Université Paris Sud 11, Orsay, France
    • Correspondence: William Vainchenker, M.D., Ph.D., INSERM U 1009, 114 rue Edouard Vaillant, 94805 Villejuif Cedex, Paris, France. Telephone: 33 1 42 11 53 63; Fax: 33 1 42 11 52 40; e-mail:verpre@igr.fr

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  • Isabelle Plo

    1. Institut National de la Santé et de la Recherche Médicale, UMR 1009, Laboratory of Excellence GR-Ex, 114 rue Edouard Vaillant, Villejuif, Paris, France
    2. Institut Gustave Roussy, Villejuif, Paris, France
    3. Université Paris Sud 11, Orsay, France
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Abstract

Ten-eleven-translocation 2 (TET2) belongs to the TET protein family that catalyzes the conversion of 5-methylcytosine into 5-hydroxymethylcytosine and plays a central role in normal and malignant adult hematopoiesis. Yet the role of TET2 in human hematopoietic development remains largely unknown. Here, we show that TET2 expression is low in human embryonic stem cell (ESC) lines and increases during hematopoietic differentiation. shRNA-mediated TET2 knockdown had no effect on the pluripotency of various ESCs. However, it skewed their differentiation into neuroectoderm at the expense of endoderm and mesoderm both in vitro and in vivo. These effects were rescued by reintroducing the targeted TET2 protein. Moreover, TET2-driven differentiation was dependent on NANOG transcriptional factor. Indeed, TET2 bound to NANOG promoter and in TET2-deficient cells the methylation of the NANOG promoter correlated with a decreased in NANOG expression. The altered differentiation resulting from TET2 knockdown in ESCs led to a decrease in both the number and the cloning capacities of hematopoietic progenitors. These defects were due to an increased apoptosis and an altered gene expression profile, including abnormal expression of neuronal genes. Intriguingly, when TET2 was knockdown in hematopoietic cells, it increased hematopoietic development. In conclusion, our work suggests that TET2 is involved in different stages of human embryonic development, including induction of the mesoderm and hematopoietic differentiation. Stem Cells 2014;32:2084–2097

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