Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization.

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Chromosomes, Human, X* ; Genomic Imprinting* ; Sex Ratio* ; X Chromosome Inactivation*; Female ; Fertilization in Vitro ; Humans
    • Abstract:
      Dynamic epigenetic reprogramming occurs during normal embryonic development at the preimplantation stage. Erroneous epigenetic modifications due to environmental perturbations such as manipulation and culture of embryos during in vitro fertilization (IVF) are linked to various short- or long-term consequences. Among these, the skewed sex ratio, an indicator of reproductive hazards, was reported in bovine and porcine embryos and even human IVF newborns. However, since the first case of sex skewing reported in 1991, the underlying mechanisms remain unclear. We reported herein that sex ratio is skewed in mouse IVF offspring, and this was a result of female-biased peri-implantation developmental defects that were originated from impaired imprinted X chromosome inactivation (iXCI) through reduced ring finger protein 12 (Rnf12)/X-inactive specific transcript (Xist) expression. Compensation of impaired iXCI by overexpression of Rnf12 to up-regulate Xist significantly rescued female-biased developmental defects and corrected sex ratio in IVF offspring. Moreover, supplementation of an epigenetic modulator retinoic acid in embryo culture medium up-regulated Rnf12/Xist expression, improved iXCI, and successfully redeemed the skewed sex ratio to nearly 50% in mouse IVF offspring. Thus, our data show that iXCI is one of the major epigenetic barriers for the developmental competence of female embryos during preimplantation stage, and targeting erroneous epigenetic modifications may provide a potential approach for preventing IVF-associated complications.
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    • Grant Information:
      R01 CA131158 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: Rnf12; X chromosome inactivation; Xist; in vitro fertilization; sex ratio
    • Publication Date:
      Date Created: 20160309 Date Completed: 20160909 Latest Revision: 20181113
    • Publication Date:
      20231215
    • Accession Number:
      PMC4812732
    • Accession Number:
      10.1073/pnas.1523538113
    • Accession Number:
      26951653