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 inProceedings of the National Academy of Sciences - PNAS Vol. 115; no. 47; pp. E11071 - E11080
Main Authors Yu, Dawei, Wang, Jing, Zou, Huiying, Feng, Tao, Chen, Lei, Li, Jia, Qi, Xiaolan, Li, Zhifang, Duan, Xiaoyue, Xu, Chunlong, Zhang, Liang, Long, Xi, Lan, Jing, Chen, Chao, Wang, Chao, Xu, Xinyu, Ren, Jilong, Zhao, Yiqiang, Hu, Xiaoxiang, Lian, Zhengxing, Men, Hongsheng, Pan, Dengke, Li, Ning, Capecchi, Mario R., Du, Xuguang, Zhao, Yaofeng, Wu, Sen
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 20.11.2018
SeriesPNAS Plus
Subjects
Animals
Biological Sciences
Cell growth
Cellular biology
Chromosomes
Cloning
DNA Methylation - genetics
Embryo Transfer - adverse effects
Embryo, Mammalian - cytology
Embryos
Female
Fetuses
Gene expression
Gene Expression Profiling
Gene Expression Regulation, Developmental - genetics
Gene silencing
Genomic Imprinting - genetics
Induced Pluripotent Stem Cells - cytology
Mammals
Nuclear transfer
Nuclear Transfer Techniques
Plague
Pluripotency
PNAS Plus
Pregnancy
Pregnancy Complications - genetics
Repressor Proteins - genetics
Restoration
Retroelements - genetics
Stem cell transplantation
Stem cells
Swine
DNA methylation
RTL1
pregnancy failure
genomic imprinting
nuclear transfer
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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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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