Undifferentiated Embryonic Cell Transcription Factor 1 Regulates ESC Chromatin Organization and Gene Expression §

Authors

  • Susanne M. Kooistra,

    1. Department of Developmental Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Haren, The Netherlands
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  • Vincent van den Boom,

    1. Department of Cell Biology, Section Stem Cell Biology, University Medical Center Groningen, Groningen, The Netherlands
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  • Rajkumar P. Thummer,

    1. Department of Developmental Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Haren, The Netherlands
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  • Frank Johannes,

    1. Groningen Bioinformatics Centre, University of Groningen, Haren, The Netherlands
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  • René Wardenaar,

    1. Groningen Bioinformatics Centre, University of Groningen, Haren, The Netherlands
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  • Bruno M. Tesson,

    1. Groningen Bioinformatics Centre, University of Groningen, Haren, The Netherlands
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  • Liesbeth M. Veenhoff,

    1. Department of Biochemistry, Netherlands Proteomics Centre, University of Groningen, Groningen, The Netherlands
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  • Fabrizia Fusetti,

    1. Department of Biochemistry, Netherlands Proteomics Centre, University of Groningen, Groningen, The Netherlands
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  • Laura P. O'Neill,

    1. Chromatin and Gene Expression Group, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom
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  • Bryan M. Turner,

    1. Chromatin and Gene Expression Group, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom
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  • Gerald de Haan,

    1. Department of Cell Biology, Section Stem Cell Biology, University Medical Center Groningen, Groningen, The Netherlands
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  • Bart J. L. Eggen

    Corresponding author
    1. Department of Developmental Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Haren, The Netherlands
    2. Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, Groningen, The Netherlands
    • Department of Developmental Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Haren, The Netherlands

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    • Telephone: +31-50-3632136; Fax: +31-50-3632751


  • Author contributions: S.M.K.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; V.v.d.B.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; R.P.T.: collection and/or assembly of data; F.J.: data analysis and interpretation; R.W.: data analysis and interpretation; B.M.T.: data analysis and interpretation; L.M.V.: collection and/or assembly of data, data analysis and interpretation; F.F.: collection and/or assembly of data, data analysis and interpretation; L.P.O.: collection and/or assembly of data, manuscript writing; B.M.T.: manuscript writing; G.d.H.: manuscript writing; B.J.L.E.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript. S.M.K. and V.v.d.B. contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLS EXPRESS August 16, 2010.

Abstract

Previous reports showed that embryonic stem (ES) cells contain hyperdynamic and globally transcribed chromatin—properties that are important for ES cell pluripotency and differentiation. Here, we demonstrate a role for undifferentiated embryonic cell transcription factor 1 (UTF1) in regulating ES cell chromatin structure. Using chromatin immunoprecipitation-on-chip analysis, we identified >1,700 UTF1 target genes that significantly overlap with previously identified Nanog, Oct4, Klf-4, c-Myc, and Rex1 targets. Gene expression profiling showed that UTF1 knock down results in increased expression of a large set of genes, including a significant number of UTF1 targets. UTF1 knock down (KD) ES cells are, irrespective of the increased expression of several self-renewal genes, Leukemia inhibitory factor (LIF) dependent. However, UTF1 KD ES cells are perturbed in their differentiation in response to dimethyl sulfoxide (DMSO) or after LIF withdrawal and display increased colony formation. UTF1 KD ES cells display extensive chromatin decondensation, reflected by a dramatic increase in nucleosome release on micrococcal nuclease (MNase) treatment and enhanced MNase sensitivity of UTF1 target genes in UTF1 KD ES cells. Summarizing, our data show that UTF1 is a key chromatin component in ES cells, preventing ES cell chromatin decondensation, and aberrant gene expression; both essential for proper initiation of lineage-specific differentiation of ES cells. STEM CELLS 2010;28:1703–1714

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