Novel STAT3 Target Genes Exert Distinct Roles in the Inhibition of Mesoderm and Endoderm Differentiation in Cooperation with Nanog

Authors

  • Pierre-Yves Bourillot,

    1. Institut National de la Santé et de la Recherche Médicale, U846, Bron, France
    2. Stem Cell and Brain Research Institute, Bron, France
    3. Université de Lyon, Lyon, France
    Search for more papers by this author
    • P.-Y.B. and I.A. contributed equally to this work.

  • Irène Aksoy,

    1. Institut National de la Santé et de la Recherche Médicale, U846, Bron, France
    2. Stem Cell and Brain Research Institute, Bron, France
    3. Université de Lyon, Lyon, France
    Search for more papers by this author
    • P.-Y.B. and I.A. contributed equally to this work.

  • Valerie Schreiber,

    1. Institut National de la Santé et de la Recherche Médicale, U846, Bron, France
    2. Stem Cell and Brain Research Institute, Bron, France
    3. Université de Lyon, Lyon, France
    Search for more papers by this author
  • Florence Wianny,

    1. Institut National de la Santé et de la Recherche Médicale, U846, Bron, France
    2. Stem Cell and Brain Research Institute, Bron, France
    3. Université de Lyon, Lyon, France
    Search for more papers by this author
  • Herbert Schulz,

    1. Max Delbrück Center for Molecular Medicine, Berlin, Germany
    Search for more papers by this author
  • Oliver Hummel,

    1. Max Delbrück Center for Molecular Medicine, Berlin, Germany
    Search for more papers by this author
  • Norbert Hubner,

    1. Max Delbrück Center for Molecular Medicine, Berlin, Germany
    Search for more papers by this author
  • Pierre Savatier

    Corresponding author
    1. Institut National de la Santé et de la Recherche Médicale, U846, Bron, France
    2. Stem Cell and Brain Research Institute, Bron, France
    3. Université de Lyon, Lyon, France
    • INSERM U846, 18 Avenue Doyen Lépine, 69500 Bron, France
    Search for more papers by this author
    • Telephone: 33-472-91-34-42; Fax: 33-472-91-34-61


  • Author contributions: P.-Y.B.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; I.A.: collection and/or assembly of data, data analysis and interpretation, final approval of manuscript; V.S., F.W.: collection of data; H.S.: collection and/or assembly of data; O.H.: collection and/or assembly of data, final approval of manuscript; N.H.: financial support, final approval of manuscript; P.S.: financial support, administrative support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • First published online in STEM CELLS EXPRESS April 30, 2009.

Abstract

Leukemia inhibitory factor (LIF) activates the transcription factor signal transducer and activator of transcription 3 (STAT3), which results in the maintenance of mouse embryonic stem cells in the pluripotent state by inhibiting both mesodermal and endodermal differentiation. How the LIF/STAT3 pathway inhibits commitment to both mesoderm and endoderm lineages is presently unknown. Using a hormone-dependent STAT3 and with microarray analysis, we identified 58 targets of STAT3 including 20 unknown genes. Functional analysis showed that 22 among the 23 STAT3 target genes analyzed contribute to the maintenance of the undifferentiated state, as evidenced by an increase in the frequency of differentiated colonies in a self-renewal assay and a concomitant elevation of early differentiation markers upon knockdown. Fourteen of them, including Dact1, Klf4, Klf5, Rgs16, Smad7, Ccrn4l, Cnnm1, Ocln, Ier3, Pim1, Cyr61, and Sgk, were also regulated by Nanog. Analysis of lineage-specific markers showed that the STAT3 target genes fell into three distinct categories, depending on their capacity to inhibit either mesoderm or endoderm differentiation or both. The identification of genes that harness self-renewal and are downstream targets of both STAT3 and Nanog shed light on the mechanisms underlying functional redundancy between STAT3 and Nanog in mouse embryonic stem cells. STEM CELLS 2009;27:1760–1771

Ancillary