A PRC2-Dependent Repressive Role of PRDM14 in Human Embryonic Stem Cells and Induced Pluripotent Stem Cell Reprogramming§

Authors

  • Yun-Shen Chan,

    1. Gene Regulation Laboratory, Genome Institute of Singapore, Singapore, Singapore
    2. Graduate School for Integrative Sciences & Engineering , National University of Singapore, Singapore, Singapore
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  • Jonathan Göke,

    1. Gene Regulation Laboratory, Genome Institute of Singapore, Singapore, Singapore
    2. Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany
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  • Xinyi Lu,

    1. Gene Regulation Laboratory, Genome Institute of Singapore, Singapore, Singapore
    2. Department of Biological Sciences, National University of Singapore, Singapore, Singapore
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  • Nandini Venkatesan,

    1. Division of Molecular Genetics and Cell Biology, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
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  • Bo Feng,

    1. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
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  • I-Hsin Su,

    Corresponding author
    1. Division of Molecular Genetics and Cell Biology, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    • Division of Molecular Genetics and Cell Biology, School of Biological Sciences, Nanyang Technological University, SBS-02n-46, 60 Nanyang Drive, Singapore 637551, Singapore
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    • Telephone: +65-65138687; Fax: +65-67913856

  • Huck-Hui Ng

    Corresponding author
    1. Gene Regulation Laboratory, Genome Institute of Singapore, Singapore, Singapore
    2. Graduate School for Integrative Sciences & Engineering , National University of Singapore, Singapore, Singapore
    3. Department of Biological Sciences, National University of Singapore, Singapore, Singapore
    4. Division of Molecular Genetics and Cell Biology, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    5. Department of Biochemistry, National University of Singapore, Singapore, Singapore
    • Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome Building, Singapore 138672, Singapore
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    • Telephone: +65-68088145; Fax: +65-68089004


  • Author contributions: Y.C.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; J.G.: collection and/or assembly of data, data analysis and interpretation, and manuscript writing; X.L., N.V., and B.F.: collection and/or assembly of data and data analysis and interpretation; I.S.: provision of study material, data analysis and interpretation, manuscript writing, and final approval of manuscript; H.N.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript.

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

  • §

    First published online in STEM CELLS EXPRESS December 28, 2012.

Abstract

PRDM14 is an important determinant of the human embryonic stem cell (ESC) identity and works in concert with the core ESC regulators to activate pluripotency-associated genes. PRDM14 has been previously reported to exhibit repressive activity in mouse ESCs and primordial germ cells; and while PRDM14 has been implicated to suppress differentiation genes in human ESCs, the exact mechanism of this repressive activity remains unknown. In this study, we provide evidence that PRDM14 is a direct repressor of developmental genes in human ESCs. PRDM14 binds to silenced genes in human ESCs and its global binding profile is enriched for the repressive trimethylation of histone H3 lysine 27 (H3K27me3) modification. Further investigation reveals that PRDM14 interacts directly with the chromatin regulator polycomb repressive complex 2 (PRC2) and PRC2 binding is detected at PRDM14-bound loci in human ESCs. Depletion of PRDM14 reduces PRC2 binding at these loci and the concomitant reduction of H3K27me3 modification. Using reporter assays, we demonstrate that gene loci bound by PRDM14 exhibit repressive activity that is dependent on both PRDM14 and PRC2. In reprogramming human fibroblasts into induced pluripotent stem cells (iPSCs), ectopically expressed PRDM14 can repress these developmental genes in fibroblasts. In addition, we show that PRDM14 recruits PRC2 to repress a key mesenchymal gene ZEB1, which enhances mesenchymal-to-epithelial transition in the initiation event of iPSC reprogramming. In summary, our study reveals a repressive role of PRDM14 in the maintenance and induction of pluripotency and identifies PRDM14 as a new regulator of PRC2. STEM CELLS 2013;31:682–692

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