Silencing of retrotransposon-derived imprinted gene RTL1 is the main cause for postimplantational failures in mammalian cloning

Proc Natl Acad Sci U S A. 2018 Nov 20;115(47):E11071-E11080. doi: 10.1073/pnas.1814514115. Epub 2018 Oct 31.

Abstract

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.

Keywords: DNA methylation; RTL1; genomic imprinting; nuclear transfer; pregnancy failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Methylation / genetics*
  • Embryo Transfer / adverse effects
  • Embryo, Mammalian / cytology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental / genetics
  • Genomic Imprinting / genetics*
  • Induced Pluripotent Stem Cells / cytology*
  • Nuclear Transfer Techniques
  • Pregnancy
  • Pregnancy Complications / genetics*
  • Repressor Proteins / genetics*
  • Retroelements / genetics*
  • Swine

Substances

  • Repressor Proteins
  • Retroelements