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Dppa3 expression is critical for generation of fully reprogrammed iPS cells and maintenance of Dlk1-Dio3 imprinting

Author

Listed:
  • Xingbo Xu

    (Institute of Human Genetics, University of Goettingen)

  • Lukasz Smorag

    (Institute of Human Genetics, University of Goettingen)

  • Toshinobu Nakamura

    (Nagahama Institute of Bio-Science and Technology)

  • Tohru Kimura

    (Kitasato University School of Science)

  • Ralf Dressel

    (University of Goettingen)

  • Antje Fitzner

    (Institute of Human Genetics, Johannes Gutenberg-University Mainz)

  • Xiaoying Tan

    (Institute of Human Genetics, University of Goettingen)

  • Matthias Linke

    (Institute of Human Genetics, Johannes Gutenberg-University Mainz)

  • Ulrich Zechner

    (Institute of Human Genetics, Johannes Gutenberg-University Mainz)

  • Wolfgang Engel

    (Institute of Human Genetics, University of Goettingen)

  • D. V. Krishna Pantakani

    (Institute of Human Genetics, University of Goettingen)

Abstract

Reprogramming of mouse somatic cells into induced pluripotent stem cells (iPSCs) often generates partially reprogrammed iPSCs (pre-iPSCs), low-grade chimera forming iPSCs (lg-iPSCs) and fully reprogrammed, high-grade chimera production competent iPSCs (hg-iPSCs). Lg-iPSC transcriptome analysis revealed misregulated Dlk1-Dio3 cluster gene expression and subsequently the imprinting defect at the Dlk1-Dio3 locus. Here, we show that germ-cell marker Dppa3 is present only in lg-iPSCs and hg-iPSCs, and that induction with exogenous Dppa3 enhances reprogramming kinetics, generating all hg-iPSCs, similar to vitamin C (Vc). Conversely, Dppa3-null fibroblasts show reprogramming block at pre-iPSCs state and Dlk1-Dio3 imprinting defect. At the molecular level, we show that Dppa3 is associated with Dlk1-Dio3 locus and identify that Dppa3 maintains imprinting by antagonizing Dnmt3a binding. Our results further show molecular parallels between Dppa3 and Vc in Dlk1-Dio3 imprinting maintenance and suggest that early activation of Dppa3 is one of the cascades through which Vc facilitates the generation of fully reprogrammed iPSCs.

Suggested Citation

  • Xingbo Xu & Lukasz Smorag & Toshinobu Nakamura & Tohru Kimura & Ralf Dressel & Antje Fitzner & Xiaoying Tan & Matthias Linke & Ulrich Zechner & Wolfgang Engel & D. V. Krishna Pantakani, 2015. "Dppa3 expression is critical for generation of fully reprogrammed iPS cells and maintenance of Dlk1-Dio3 imprinting," Nature Communications, Nature, vol. 6(1), pages 1-11, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7008
    DOI: 10.1038/ncomms7008
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    Cited by:

    1. Wenjing Bai & Jinxin Xu & Wenbin Gu & Danyang Wang & Ying Cui & Weidong Rong & Xiaoan Du & Xiaoxia Li & Cuicui Xia & Qingqing Gan & Guantao He & Huahui Guo & Jinfeng Deng & Yuqiong Wu & Ray-Whay Chiu , 2025. "Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy," Nature Communications, Nature, vol. 16(1), pages 1-22, December.

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