Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells

Edward J. Grow, Ryan A. Flynn, Shawn Chavez, Nicholas L. Bayless, Mark Wossidlo, Daniel J. Wesche, Lance Martin, Carol B. Ware, Catherine A. Blish, Howard Y. Chang, Renee A Reijo Pera, Joanna Wysocka

    Research output: Contribution to journalArticle

    194 Citations (Scopus)

    Abstract

    Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections, and comprise nearly 8% of the human genome. The most recently acquired human ERV is HERVK(HML-2), which repeatedly infected the primate lineage both before and after the divergence of the human and chimpanzee common ancestor. Unlike most other human ERVs, HERVK retained multiple copies of intact open reading frames encoding retroviral proteins. However, HERVK is transcriptionally silenced by the host, with the exception of in certain pathological contexts such as germ-cell tumours, melanoma or human immunodeficiency virus (HIV) infection. Here we demonstrate that DNA hypomethylation at long terminal repeat elements representing the most recent genomic integrations, together with transactivation by OCT4 (also known as POU5F1), synergistically facilitate HERVK expression. Consequently, HERVK is transcribed during normal human embryogenesis, beginning with embryonic genome activation at the eight-cell stage, continuing through the emergence of epiblast cells in preimplantation blastocysts, and ceasing during human embryonic stem cell derivation from blastocyst outgrowths. Remarkably, we detected HERVK viral-like particles and Gag proteins in human blastocysts, indicating that early human development proceeds in the presence of retroviral products. We further show that overexpression of one such product, the HERVK accessory protein Rec, in a pluripotent cell line is sufficient to increase IFITM1 levels on the cell surface and inhibit viral infection, suggesting at least one mechanism through which HERVK can induce viral restriction pathways in early embryonic cells. Moreover, Rec directly binds a subset of cellular RNAs and modulates their ribosome occupancy, indicating that complex interactions between retroviral proteins and host factors can fine-tune pathways of early human development.

    Original languageEnglish (US)
    Pages (from-to)221-246
    Number of pages26
    JournalNature
    Volume522
    Issue number7555
    DOIs
    StatePublished - Jun 11 2015

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    Blastocyst
    Endogenous Retroviruses
    Human Development
    Virus Diseases
    Integration Host Factors
    gag Gene Products
    Germ Layers
    Pan troglodytes
    Terminal Repeat Sequences
    Germ Cell and Embryonal Neoplasms
    Human Genome
    Ribosomes
    Virion
    Primates
    Transcriptional Activation
    Open Reading Frames
    Embryonic Development
    Melanoma
    Proteins
    HIV

    ASJC Scopus subject areas

    • General

    Cite this

    Grow, E. J., Flynn, R. A., Chavez, S., Bayless, N. L., Wossidlo, M., Wesche, D. J., ... Wysocka, J. (2015). Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. Nature, 522(7555), 221-246. https://doi.org/10.1038/nature14308

    Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. / Grow, Edward J.; Flynn, Ryan A.; Chavez, Shawn; Bayless, Nicholas L.; Wossidlo, Mark; Wesche, Daniel J.; Martin, Lance; Ware, Carol B.; Blish, Catherine A.; Chang, Howard Y.; Pera, Renee A Reijo; Wysocka, Joanna.

    In: Nature, Vol. 522, No. 7555, 11.06.2015, p. 221-246.

    Research output: Contribution to journalArticle

    Grow, EJ, Flynn, RA, Chavez, S, Bayless, NL, Wossidlo, M, Wesche, DJ, Martin, L, Ware, CB, Blish, CA, Chang, HY, Pera, RAR & Wysocka, J 2015, 'Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells', Nature, vol. 522, no. 7555, pp. 221-246. https://doi.org/10.1038/nature14308
    Grow EJ, Flynn RA, Chavez S, Bayless NL, Wossidlo M, Wesche DJ et al. Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. Nature. 2015 Jun 11;522(7555):221-246. https://doi.org/10.1038/nature14308
    Grow, Edward J. ; Flynn, Ryan A. ; Chavez, Shawn ; Bayless, Nicholas L. ; Wossidlo, Mark ; Wesche, Daniel J. ; Martin, Lance ; Ware, Carol B. ; Blish, Catherine A. ; Chang, Howard Y. ; Pera, Renee A Reijo ; Wysocka, Joanna. / Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. In: Nature. 2015 ; Vol. 522, No. 7555. pp. 221-246.
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    AU - Wesche, Daniel J.

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