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Nat Commun. 2015 Jan 23;6:6008. doi: 10.1038/ncomms7008.

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

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Institute of Human Genetics, University of Goettingen, Heinrich-Dueker-Weg 12, 37073 Goettingen, Germany.
Department of Bio-Science, Nagahama Institute of Bio-Science and Technology, Shiga 526-0829, Japan.
Department of Biosciences, Kitasato University School of Science, Kanagawa 252-0373, Japan.
Department of Cellular and Molecular Immunology, University of Goettingen, Humboldtallee 34, 37073 Goettingen, Germany.
Institute of Human Genetics, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.


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.

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