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

Xingbo Xu, Lukasz Smorag, Toshinobu Nakamura, Tohru Kimura, Ralf Dressel, Antje Fitzner, Xiaoying Tan, Matthias Linke, Ulrich Zechner, Wolfgang Engel and D. V. Krishna Pantakani ()
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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

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7008

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