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Acute deletion of TET enzymes results in aneuploidy in mouse embryonic stem cells through decreased expression of Khdc3

Author

Listed:
  • Romain O. Georges

    (La Jolla Institute for Immunology)

  • Hugo Sepulveda

    (La Jolla Institute for Immunology)

  • J. Carlos Angel

    (La Jolla Institute for Immunology)

  • Eric Johnson

    (La Jolla Institute for Immunology)

  • Susan Palomino

    (La Jolla Institute for Immunology)

  • Roberta B. Nowak

    (La Jolla Institute for Immunology)

  • Arshad Desai

    (University of California, San Diego
    University of California, San Diego)

  • Isaac F. López-Moyado

    (La Jolla Institute for Immunology
    Sanford Consortium for Regenerative Medicine)

  • Anjana Rao

    (La Jolla Institute for Immunology
    Sanford Consortium for Regenerative Medicine
    University of California)

Abstract

TET (Ten-Eleven Translocation) dioxygenases effect DNA demethylation through successive oxidation of the methyl group of 5-methylcytosine (5mC) in DNA. In humans and in mouse models, TET loss-of-function has been linked to DNA damage, genome instability and oncogenesis. Here we show that acute deletion of all three Tet genes, after brief exposure of triple-floxed, Cre-ERT2-expressing mouse embryonic stem cells (mESC) to 4-hydroxytamoxifen, results in chromosome mis-segregation and aneuploidy; moreover, embryos lacking all three TET proteins showed striking variation in blastomere numbers and nuclear morphology at the 8-cell stage. Transcriptional profiling revealed that mRNA encoding a KH-domain protein, Khdc3 (Filia), was downregulated in triple TET-deficient mESC, concomitantly with increased methylation of CpG dinucleotides in the vicinity of the Khdc3 gene. Restoring KHDC3 levels in triple Tet-deficient mESC prevented aneuploidy. Thus, TET proteins regulate Khdc3 gene expression, and TET deficiency results in mitotic infidelity and genome instability in mESC at least partly through decreased expression of KHDC3.

Suggested Citation

  • Romain O. Georges & Hugo Sepulveda & J. Carlos Angel & Eric Johnson & Susan Palomino & Roberta B. Nowak & Arshad Desai & Isaac F. López-Moyado & Anjana Rao, 2022. "Acute deletion of TET enzymes results in aneuploidy in mouse embryonic stem cells through decreased expression of Khdc3," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33742-7
    DOI: 10.1038/s41467-022-33742-7
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