A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development. Homo sapiens

Primordial germ cells (PGCs), the embryonic precursors of sperm and ova, undergo comprehensive epigenetic reprogramming, including DNA demethylation. The detailed dynamics of epigenome resetting in the human germline is largely unknown. Here, we studied transcriptome transitions and epigenetic reprogramming in developmental week 5-9 in vivo human hPGCs (hPGCs) and nascent hPGC-like cells hPGCLCs by RNA-sequencing (RNA-Seq) and whole-genome bisulfite sequencing (BS-Seq). We found that the transcriptional program of hPGCs is distinct from that in mice, with co-expression of somatic specifiers and naïve pluripotency genes. Base-resolution hPGC methylome analysis revealed progressive DNA demethylation to basal levels by week 7. Despite global hypomethylation, some loci associated with metabolic and neurological disorders are resistant to DNA demethylation, revealing potential for transgenerational epigenetic inheritance