The ghost in the machine

The human genome bears traces of past retroviral infections in the form of endogenous retroviruses (ERVs) whose long terminal repeats (LTRs) contain cis-regulatory elements that affect gene activity. The evolutionarily most recent memberof the human ERV family, HERVK, retains intact open reading frames (ORFs) encoding retroviral proteins that are normally silenced by DNA methylation. Now Wysocka and colleagues show that HERVK transcription is activated during human embryogenesis, with likely effects on early development. Analysis of single-cell RNA-sequencing profiles at different embryonic stages revealed active HERVK transcriptionat the eight-cell stage and in epiblast cells (ECs) of the preimplantation blastocyst; this transcription is then silenced upon blastocyst outgrowth. Similarly, HERVK transcripts are present in naive human embryonic stem cells (ESCs) that correspond to the preimplantation state but not in primed ESCs, thus suggesting that HERVK expression is induced during a transient window when DNA is hypomethylated and regulatory elements are accessible to the pluripotency factors OCT4 and SOX2. Indeed, the authors show that the LTR of HERVK contains an OCT4-binding motif that is engaged by the transcription factor in ECs but not primed ESCs. DNA hypomethylation is required for OCT4-dependent activation, which promotes stage-specific expression of proviral proteins. Most remarkably, transmission electron microscopy shows that human blastocysts contain numerous viral-like particles.