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Research Article

Dynamic regulation of human endogenous retroviruses mediates factor-induced reprogramming and differentiation potential

Mari Ohnuki, Koji Tanabe, Kenta Sutou, Ito Teramoto, Yuka Sawamura, Megumi Narita, Michiko Nakamura, Yumie Tokunaga, Masahiro Nakamura, Akira Watanabe, Shinya Yamanaka, and Kazutoshi Takahashi
  1. aCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and
  2. bGladstone Institute of Cardiovascular Disease, San Francisco, California 94158

See allHide authors and affiliations

PNAS August 26, 2014 111 (34) 12426-12431; first published August 5, 2014; https://doi.org/10.1073/pnas.1413299111
Mari Ohnuki
aCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and
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Koji Tanabe
aCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and
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Kenta Sutou
aCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and
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Ito Teramoto
aCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and
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Yuka Sawamura
aCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and
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Megumi Narita
aCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and
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Michiko Nakamura
aCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and
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Yumie Tokunaga
aCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and
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Masahiro Nakamura
aCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and
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Akira Watanabe
aCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and
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Shinya Yamanaka
aCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and
bGladstone Institute of Cardiovascular Disease, San Francisco, California 94158
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  • For correspondence: yamanaka@cira.kyoto-u.ac.jp takahash@cira.kyoto-u.ac.jp
Kazutoshi Takahashi
aCenter for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; and
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  • For correspondence: yamanaka@cira.kyoto-u.ac.jp takahash@cira.kyoto-u.ac.jp
  1. Contributed by Shinya Yamanaka, July 14, 2014 (sent for review June 6, 2014; reviewed by Konrad Hochedlinger)

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Significance

In this study, we found that human endogenous retoriviruses type-H (HERV-Hs) are transiently hyperactivated during reprogramming toward induced pluripotent stem cells (iPSCs) and play important roles in this process. However, when reprogramming is complete and cells acquire full pluripotency, HERV-H activity should decrease to levels comparable with those in embryonic stem cells because failure to resilence this activity leads to the differentiation-defective phenotype in neural lineage. We also found that during reprogramming, reprogramming factors, including POU class 5 homeobox 1 (OCT3/4), sex determining region Y-box 2 (SOX2), and Krüppel-like factor 4 (KLF4) (OSK) bind to and activate long-terminal repeats of HERV-Hs. KLF4 possibly precludes Tripartite motif containing 28 and recruits not only OCT3/4 and SOX2, but also E1A binding protein p300 (p300) histone acethyltransferase on HERV-H loci. Therefore, OKSM-induced HERV-H activation constitutes an unanticipated and critical mechanism for iPSC formation.

Abstract

Pluripotency can be induced in somatic cells by overexpressing transcription factors, including POU class 5 homeobox 1 (OCT3/4), sex determining region Y-box 2 (SOX2), Krüppel-like factor 4 (KLF4), and myelocytomatosis oncogene (c-MYC). However, some induced pluripotent stem cells (iPSCs) exhibit defective differentiation and inappropriate maintenance of pluripotency features. Here we show that dynamic regulation of human endogenous retroviruses (HERVs) is important in the reprogramming process toward iPSCs, and in re-establishment of differentiation potential. During reprogramming, OCT3/4, SOX2, and KLF4 transiently hyperactivated LTR7s—the long-terminal repeats of HERV type-H (HERV-H)—to levels much higher than in embryonic stem cells by direct occupation of LTR7 sites genome-wide. Knocking down LTR7s or long intergenic non-protein coding RNA, regulator of reprogramming (lincRNA-RoR), a HERV-H–driven long noncoding RNA, early in reprogramming markedly reduced the efficiency of iPSC generation. KLF4 and LTR7 expression decreased to levels comparable with embryonic stem cells once reprogramming was complete, but failure to resuppress KLF4 and LTR7s resulted in defective differentiation. We also observed defective differentiation and LTR7 activation when iPSCs had forced expression of KLF4. However, when aberrantly expressed KLF4 or LTR7s were suppressed in defective iPSCs, normal differentiation was restored. Thus, a major mechanism by which OCT3/4, SOX2, and KLF4 promote human iPSC generation and reestablish potential for differentiation is by dynamically regulating HERV-H LTR7s.

  • retrotransposon
  • epigenetics
  • evolution

Footnotes

  • ↵1Present address: Anthropology and Human Genetics Department Biology II, Ludwig Maximilians University Munich, 82152 Martinsried, Germany.

  • ↵2Present address: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, California 94305.

  • ↵3To whom correspondence may be addressed. Email: yamanaka{at}cira.kyoto-u.ac.jp or takahash{at}cira.kyoto-u.ac.jp.
  • Author contributions: S.Y. and K. Takahashi designed research; M.O., K. Tanabe, K.S., I.T., Y.S., M. Narita., Michiko Nakamura, and K. Takahashi performed research; M.O., Y.T., Masahiro Nakamura, A.W., and K. Takahashi analyzed data; K. Tanabe contributed new reagents/analytic tools; and S.Y. and K. Takahashi wrote the paper.

  • Reviewers included: K.H., Howard Hughes Medical Institute and Massachusetts General Hospital Cancer Center.

  • Conflict of interest statement: S.Y. is a member without salary of the scientific advisory board of iPS Academia Japan.

  • Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession nos. GSE54848 and GSE56569).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1413299111/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Role of HERV-H during reprogramming
Mari Ohnuki, Koji Tanabe, Kenta Sutou, Ito Teramoto, Yuka Sawamura, Megumi Narita, Michiko Nakamura, Yumie Tokunaga, Masahiro Nakamura, Akira Watanabe, Shinya Yamanaka, Kazutoshi Takahashi
Proceedings of the National Academy of Sciences Aug 2014, 111 (34) 12426-12431; DOI: 10.1073/pnas.1413299111

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Role of HERV-H during reprogramming
Mari Ohnuki, Koji Tanabe, Kenta Sutou, Ito Teramoto, Yuka Sawamura, Megumi Narita, Michiko Nakamura, Yumie Tokunaga, Masahiro Nakamura, Akira Watanabe, Shinya Yamanaka, Kazutoshi Takahashi
Proceedings of the National Academy of Sciences Aug 2014, 111 (34) 12426-12431; DOI: 10.1073/pnas.1413299111
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