CARM1 Is Required in Embryonic Stem Cells to Maintain Pluripotency and Resist Differentiation

Authors

  • Qiang Wu,

    1. Wellcome Trust and Cancer Research UK Gurdon Institute, Cambridge, United Kingdom
    2. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Current affiliation:
    1. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, MD7 #02-06, Singapore 117597
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    • Q.W. and A.W.B. provided equal contributions.

  • Alexander W. Bruce,

    1. Wellcome Trust and Cancer Research UK Gurdon Institute, Cambridge, United Kingdom
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    • Q.W. and A.W.B. provided equal contributions.

  • Agnieszka Jedrusik,

    1. Wellcome Trust and Cancer Research UK Gurdon Institute, Cambridge, United Kingdom
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  • Peter D. Ellis,

    1. The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom
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  • Robert M. Andrews,

    1. The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom
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  • Cordelia F. Langford,

    1. The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom
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  • David M. Glover,

    Corresponding author
    1. Cancer Research UK Cell Cycle Genetics Research Group, University of Cambridge, Department of Genetics, Cambridge, United Kingdom
    • Cancer Research UK Cell Cycle Genetics Research Group, University of Cambridge, Department of Genetics, Downing Street, Cambridge, CB2 3EH, UK
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    • Telephone: +44 1223 333988; Fax: +44 333992

  • Magdalena Zernicka-Goetz

    Corresponding author
    1. Wellcome Trust and Cancer Research UK Gurdon Institute, Cambridge, United Kingdom
    2. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    • Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
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    • Telephone: +44 1223 763291; Fax: +44 1223 334089


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

  • First published online in STEM CELLS EXPRESS May 21, 2009; available online without subscription throught the open access option.

Abstract

Histone H3 methylation at R17 and R26 recently emerged as a novel epigenetic mechanism regulating pluripotency in mouse embryos. Blastomeres of four-cell embryos with high H3 methylation at these sites show unrestricted potential, whereas those with lower levels cannot support development when aggregated in chimeras of like cells. Increasing histone H3 methylation, through expression of coactivator-associated-protein-arginine-methyltransferase 1 (CARM1) in embryos, elevates expression of key pluripotency genes and directs cells to the pluripotent inner cell mass. We demonstrate CARM1 is also required for the self-renewal and pluripotency of embryonic stem (ES) cells. In ES cells, CARM1 depletion downregulates pluripotency genes leading to their differentiation. CARM1 associates with Oct4/Pou5f1 and Sox2 promoters that display detectable levels of R17/26 histone H3 methylation. In CARM1 overexpressing ES cells, histone H3 arginine methylation is also at the Nanog promoter to which CARM1 now associates. Such cells express Nanog at elevated levels and delay their response to differentiation signals. Thus, like in four-cell embryo blastomeres, histone H3 arginine methylation by CARM1 in ES cells allows epigenetic modulation of pluripotency. STEM CELLS 2009;27:2637–2645

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