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MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency

Author

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  • Alexandre Gaspar-Maia

    (Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA
    Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai 1425 Madison Avenue, New York, New York 10029, USA)

  • Zulekha A. Qadeer

    (Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA
    Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai 1425 Madison Avenue, New York, New York 10029, USA
    Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA)

  • Dan Hasson

    (Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA
    Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA)

  • Kajan Ratnakumar

    (Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA
    Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai 1425 Madison Avenue, New York, New York 10029, USA
    Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA)

  • N. Adrian Leu

    (School of Veterinary Medicine, University of Pennsylvania)

  • Gary Leroy

    (Princeton University, 415 Schultz Laboratory)

  • Shichong Liu

    (Princeton University, 415 Schultz Laboratory
    Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, 1009C Stellar-Chance Laboratories 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA)

  • Carl Costanzi

    (School of Veterinary Medicine, University of Pennsylvania)

  • David Valle-Garcia

    (Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA
    Institute for Cellular Physiology, National Autonomous University of Mexico)

  • Christoph Schaniel

    (Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai 1425 Madison Avenue, New York, New York 10029, USA
    Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA)

  • Ihor Lemischka

    (Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai 1425 Madison Avenue, New York, New York 10029, USA
    Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA
    Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA
    Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA)

  • Benjamin Garcia

    (Princeton University, 415 Schultz Laboratory
    Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, 1009C Stellar-Chance Laboratories 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA)

  • John R. Pehrson

    (School of Veterinary Medicine, University of Pennsylvania)

  • Emily Bernstein

    (Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA
    Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai 1425 Madison Avenue, New York, New York 10029, USA
    Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA)

Abstract

The chromatin template imposes an epigenetic barrier during the process of somatic cell reprogramming. Using fibroblasts derived from macroH2A double knockout (dKO) mice, here we show that these histone variants act cooperatively as a barrier to induced pluripotency. Through manipulation of macroH2A isoforms, we further demonstrate that macroH2A2 is the predominant barrier to reprogramming. Genomic analyses reveal that macroH2A1 and macroH2A2, together with H3K27me3, co-occupy pluripotency genes in wild-type (wt) fibroblasts. In particular, we find macroH2A isoforms to be highly enriched at target genes of the K27me3 demethylase, Utx, which are reactivated early in iPS reprogramming. Finally, while macroH2A dKO-induced pluripotent cells are able to differentiate properly in vitro and in vivo, such differentiated cells retain the ability to return to a stem-like state. Therefore, we propose that macroH2A isoforms provide a redundant silencing layer or terminal differentiation ‘lock’ at critical pluripotency genes that presents as an epigenetic barrier when differentiated cells are challenged to reprogram.

Suggested Citation

  • Alexandre Gaspar-Maia & Zulekha A. Qadeer & Dan Hasson & Kajan Ratnakumar & N. Adrian Leu & Gary Leroy & Shichong Liu & Carl Costanzi & David Valle-Garcia & Christoph Schaniel & Ihor Lemischka & Benja, 2013. "MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency," Nature Communications, Nature, vol. 4(1), pages 1-13, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2582
    DOI: 10.1038/ncomms2582
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