Format

Send to

Choose Destination
Nature. 2015 Jun 11;522(7555):221-5. doi: 10.1038/nature14308. Epub 2015 Apr 20.

Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells.

Author information

1
Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
2
Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
3
1] Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [2] Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [3] Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, Beaverton, Oregon 97006, USA.
4
Stanford Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
5
1] Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA [2] Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [3] Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA.
6
Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA.
7
Department of Comparative Medicine, University of Washington, Seattle, Washington 98195-8056, USA.
8
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
9
1] Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA [2] Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [3] Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [4] Department of Cell Biology and Neurosciences, Montana State University, Bozeman, Montana 59717, USA.
10
1] Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [2] Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA [3] Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA.

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.

PMID:
25896322
PMCID:
PMC4503379
DOI:
10.1038/nature14308
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center