Human Reproduction is Regulated by Retrotransposons derived from Ancient Hominin-Specific Viral Infections

Abstract Germ cells are essential to pass DNA from one generation to the next. In human reproduction, germ cell development begins with the specification of primordial germ cells (PGCs) and a failure to specify PGCs leads to human infertility. Recent studies have revealed that the transcription factor network required for PGC specification has diverged in mammals, and this has a significant impact on our understanding of human reproduction. Here, we evaluated the emerging epigenetic landscape during hPGC specification using a combination of in vivo and in vitro analysis of hPGCs/hPGC-like cells (hPGCLCs) and human embryonic stem cells (hESCs). Our data reveals that hominid restricted Transposable Elements (TEs) partly derived from ancient viruses are pre-bound by the transcription factors TFAP2C and NANOG in undifferentiated hESCs, become transcriptionally induced during PGC specification and undergo dynamic epigenetic reprogramming leading to increased chromatin accessibility, localized DNA demethylation and establishment of broad peaks of H3K27ac. Using KRAB mediated CRISPRi we show that blocking this remodeling has a significant impact on hPGC specification. In summary, our data reveals that human reproduction requires the establishment of an epigenetic landscape during hPGC specification driven by the acquisition of hominid-specific TEs that were derived from ancient viral infections that entered the hominid germline less than 5 million years ago.