title: Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells.
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.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Grow
authors.affiliation: Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Flynn
authors.affiliation: 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.
authors.forename: Shawn L
authors.initials: SL
authors.lastname: Chavez
authors.affiliation: Stanford Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Bayless
authors.affiliation: 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.
authors.forename: Mark
authors.initials: M
authors.lastname: Wossidlo
authors.affiliation: Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wesche
authors.affiliation: Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Lance
authors.initials: L
authors.lastname: Martin
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington 98195-8056, USA.
authors.forename: Carol B
authors.initials: CB
authors.lastname: Ware
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Blish
authors.affiliation: Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Renee A Reijo
authors.initials: RA
authors.lastname: Pera
authors.affiliation: 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.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wysocka
mesh_terms: D000943:Antigens, Differentiation / Q000378:metabolism; D001755:Blastocyst / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D002460:Cell Line; D019175:DNA Methylation; D020077:Endogenous Retroviruses / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015683:Gene Products, gag / Q000378:metabolism; D006801:Humans; D008297:Male; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D016366:Open Reading Frames / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism; D020079:Terminal Repeat Sequences / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation
chemical_list: D000943:Antigens, Differentiation; C485839:ERVK-6 protein, human endogenous retrovirus; D015683:Gene Products, gag; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D012333:RNA, Messenger; D014759:Viral Envelope Proteins; C062010:leu-13 antigen