DNA Demethylation Dynamics in the Human Prenatal Germline

Global DNA demethylation in humans is a fundamental process that occurs in pre-implantation embryos and reversion to naive ground state pluripotent stem cells (PSCs). However, the extent of DNA methylation reprogramming in human germline cells is unknown. Here, we performed whole-genome bisulfite sequencing (WGBS) and RNA-sequencing (RNA-seq) of human prenatal germline cells from 53 to 137 days of development. We discovered that the transcriptome and methylome of human germline is distinct from both human PSCs and the inner cell mass (ICM) of human blastocysts. Using this resource to monitor the outcome of global DNA demethylation with reversion of primed PSCs to the naive ground state, we uncovered hotspots of ultralow methylation at transposons that are protected from demethylation in the germline and ICM. Taken together, the human germline serves as a valuable in vivo tool for monitoring the epigenome of cells that have emerged from a global DNA demethylation event. [Display omitted] •Single-base-resolution methylome resource for human prenatal germline cells•Comprehensive transcriptional resource for human prenatal germline cells•Human germline is distinct from inner cell mass and naive pluripotent stem cells•Naive human pluripotent stem cells have hotspots of unbridled DNA demethylation DNA methylome and transcriptome have been profiled in developing prenatal germline cells, and global changes in gene expression do not correlate with global changes in DNA methylation.