Parental allele specific single-cell transcriptome dynamics reveal incomplete epigenetic reprogramming in human female germ cells

In contrast to mouse, human female germ cells develop asynchronously. Germ cells transition to meiosis, erase genomic imprints, and reactivate the X chromosome. It is unknown if these events all appear asynchronously, and how they relate to each other. Here we combine exome sequencing of human fetal and maternal tissues with single-cell RNA-sequencing of five donors. We reconstruct full parental haplotypes and quantify changes in parental allele specific expression, genome-wide. First we distinguish PGC, pre-meiotic, and meiotic transcriptional stages. Next we demonstrate that germ cells from various stages monoallelically express imprinted genes from e.g. the SNURF-SNRPN cluster and confirm it by methylation patterns. Finally we show that ±30% of the PGCs, are still reactivating their inactive X chromosome and that this is related to transcriptional stage, and not to embryonic age. Altogether, we reveal the complexity and cell-to-cell heterogeneity of transcriptional and epigenetic remodelling in female human germ cells. Overall design: RNA sequences from human gonadal (N=73) and adrenal cells (N=35) from the mentioned fetuses 8.1-14.4wk of development (equivalent to 10.1-16.4 weeks of gestation) using SMART-seq2.