Our genomes are littered with tales of our evolutionary past, including infections from retroviruses that have left their mark in the vast expanses of the human genome. While most of the endogenous retroviruses (ERVs) have lost their protein coding potential, a class of human specific ERVs (HERVs) still possess intact open reading frames. Inspired by the finding that other related repeat elements get activated during early embryogenesis, a group of talented researchers led by Joanna Wysocka, set out to investigate the function of the most recently acquired HERVs.
By analyzing published single-cell RNA-seq data of various stages of preimplantation embryogenesis for the expression of repetitive sequences, the researchers identify a large group of HERVs that are expressed in a stage-specific manner. Zooming in on HERVK, from which multiple insertions still harbour intact open reading frames (ORFs), the researchers uncover some remarkable features of this the most recently acquired HERV:
- HERVK expression starts shortly after embryonic genome activation (8-cell stage).
- Expression continues in epiblast cells of the blastocyst but is silenced in primed human embryonic stem cells (ESCs).
- OCT4 binds to the long terminal repeat (LTR) 5HS sequence of HERVK and regulates its expression.
- In ESCs LTR5HS in silenced by DNA methylation, preventing its activation even in the presence of OCT4.
- Induction of HERVK transcription leads to the expression of retroviral proteins and formation of viral like particles.
- Nuclear export of viral RNAs by the small accessory protein Rec triggers the innate antiviral immune response and prevents retroviral (re-)infection of the host cell.
- Rec also interacts with 3’ UTRs of host mRNAs and influences their translation efficiency.
Based on these findings the researchers extrapolate that a similar activation of HERVK could also be present during germ cell development, which is characterized by global DNA hypomethylation and the expression of OCT4. They further suggest that the HERVK-triggered innate immune response could be an evolutionarily conserved mechanism to protect embryos and germ cells from (retro-)viral infection.
Go and check out all the infectious details over at Nature, April 2015.