Epigenetic reprogramming in the mammalian germline

The role of the germline is to transmit genetic and epigenetic information from one generation to the next. Primordial germ cells (PGCs) are the pioneering germ cell population in mammals and exist for a relatively short period of time during gestation. PGCs are induced from the epiblast by bone morphogenetic protein 4 (BMP4) signaling. These definitive PGCs then migrate from their site of origin to the developing gonad during gestation. After colonization and sex-determination, they start to differentiate into male and female germ cells, which then become gametes upon spermatogenic and oogenic instructions from the niche. Since PGCs are the only embryonic cell type that is capable of differentiating into gametes, monitoring the epigenome and transcriptome of PGCs could provide important insights into the cell and molecular foundation of germline development and healthy gametes. Even though genetic information from the parental gametes is mostly maintained after fertilization and creation of the diploid embryo, the epigenome is reprogrammed with one of the major events involving the genome-wide reprogramming of DNA demethylation. A second reprogramming event in PGCs is hypothesized to remove the memory of embryo development in the epiblast. Understanding the dynamics of epigenome reprogramming in PGCs could therefore help to detect any environmental effects potentially associating with infertility or abnormal child health. The dynamics of DNA methylation reprogramming in mouse PGCs was first established by Seisenberger et al in 2012 [1]. They collected germ cells across key stages of development including PGCs from embryonic day (E) 9.5 to E13.5, E16.5 germ cells, and E6.5 epiblasts. The CpG methylation level in E6.5 epiblasts was 71%, close to the 74% in embryonic stem cell (ESCs), and droped globally during PGC expansion and migration. The CpG methylation reached the lowest level at E13.5 with an average of 14% in male and 7% in female PGCs. They found that imprinting loci, CpG islands on the X chromosome and germline-specific genes are demethylated late upon entry of PGCs into the gonads between E11.5-E13.5. There is a very limited relationship between loss of DNA methylation and gain in gene expression, including expression of transposons. In a second comprehensive study Kobayashi et al used a post-bisulfite adaptor tagging (PBAT) method with scaled-down amounts of DNA from mouse germ cells at E10.5 to E16.5 [2]. This group observed a similar pattern of global DNA demethylation and de novo methylation during PGC development. Specifically, in mouse, after E16.5 only …