Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte

Gonadal germline epigenetic reprogramming involves an interplay between DNA methylation, the polycomb complex and Tet1 in both DNA methylation dependent and independent roles, to ensure the activation of a specific subset of genes critical for progression of gametogenesis. Epigenetic reprogramming in gametogenesis During mouse embryonic development, the primordial germ cells migrate into the developing gonad, where they undergo extensive epigenetic reprogramming including loss of DNA methylation. Petra Hajkova and colleagues investigate the molecular mechanisms of this process and find that reprogramming enables the activation of a set of genes that are important for progression towards gametogenesis. The findings also reveal a complex role for the TET1 enzyme, which helps to maintain, but does not drive, the majority of genome-wide DNA demethylation that occurs in gonadal primordial germ cells. Gametes are highly specialized cells that can give rise to the next generation through their ability to generate a totipotent zygote. In mice, germ cells are first specified in the developing embryo around embryonic day (E) 6.25 as primordial germ cells (PGCs) 1 . Following subsequent migration into the developing gonad, PGCs undergo a wave of extensive epigenetic reprogramming around E10.5–E11.5 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , including genome-wide loss of 5-methylcytosine 2 , 3 , 4 , 5 , 7 , 8 , 9 , 10 , 11 . The underlying molecular mechanisms of this process have remained unclear, leading to our inability to recapitulate this step of germline development in vitro 12 , 13 , 14 . Here we show, using an integrative approach, that this complex reprogramming process involves coordinated interplay among promoter sequence characteristics, DNA (de)methylation, the polycomb (PRC1) complex and both DNA demethylation-dependent and -independent functions of TET1 to enable the activation of a critical set of germline reprogramming-responsive genes involved in gamete generation and meiosis. Our results also reveal an unexpected role for TET1 in maintaining but not driving DNA demethylation in gonadal PGCs. Collectively, our work uncovers a fundamental biological role for gonadal germline reprogramming and identifies the epigenetic principles of the PGC-to-gonocyte transition that will help to guide attempts to recapitulate complete gametogenesis in vitro .