Silencing of retrotransposon-derived imprinted gene RTL1 is the main cause for postimplantational failures in mammalian cloning
Substantial rates of fetal loss plague all in vitro procedures involving embryo manipulations, including human-assisted reproduction, and are especially problematic for mammalian cloning where over 90% of reconstructed nuclear transfer embryos are typically lost during pregnancy. However, the epigen...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 47; pp. E11071 - E11080 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
20.11.2018
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Series | PNAS Plus |
Subjects | |
Online Access | Get full text |
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Summary: | Substantial rates of fetal loss plague all in vitro procedures involving embryo manipulations, including human-assisted reproduction, and are especially problematic for mammalian cloning where over 90% of reconstructed nuclear transfer embryos are typically lost during pregnancy. However, the epigenetic mechanism of these pregnancy failures has not been well described. Here we performed methylome and transcriptome analyses of pig induced pluripotent stem cells and associated cloned embryos, and revealed that aberrant silencing of imprinted genes, in particular the retrotransposon-derived RTL1 gene, is the principal epigenetic cause of pregnancy failure. Remarkably, restoration of RTL1 expression in pig induced pluripotent stem cells rescued fetal loss. Furthermore, in other mammals, including humans, low RTL1 levels appear to be the main epigenetic cause of pregnancy failure. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Contributed by Mario Capecchi, September 25, 2018 (sent for review August 31, 2018; reviewed by Juan Carlos Izpisúa Belmonte and Jeanne F. Loring) 1D.Y., J.W., H.Z., and T.F. contributed equally to this work. Author contributions: X. Du, Yaofeng Zhao, and S.W. designed research; D.Y., J.W., H.Z., T.F., L.C., J. Li, X.Q., Z. Li, X. Duan, C.X., L.Z., X.L., J. Lan, C.C., C.W., X.X., J.R., and X. Du performed research; Yiqiang Zhao, X.H., Z. Lian, H.M., D.P., and N.L. contributed new reagents/analytic tools; D.Y., J.W., H.Z., T.F., L.C., J. Li, X.Q., Z. Li, X. Duan, C.X., L.Z., X.L., J. Lan, C.C., C.W., X.X., J.R., M.R.C., and X. Du analyzed data; and D.Y., J.W., H.Z., T.F., X. Du, M.R.C., Yaofeng Zhao, and S.W. wrote the paper. Reviewers: J.C.I.B., The Salk Institute for Biological Studies; and J.F.L., Scripps Research Institute. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1814514115 |