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–E11.52,3,4,5,6,7,8,9,10,11, including genome-wide loss of 5-methylcytosine2,3,4,5,7,8,9,10,11. The underlying molecular mechanisms of this process have remained unclear, leading to our inability to recapitulate this step of germline development in vitro12,13,14. 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.
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Gene Expression Omnibus
We thank J. Elliot and T. Adejumo for help with fluorescence activated cell sorting, L. Game for help with next-generation sequencing, F. Krueger for providing consensus repetitive element sequences, M. Woodberry, A. Cameron, and J. Glegola for mouse husbandry, T. Carell for a gift of isotopically labelled deoxynucleoside standards and the members of the Hajkova laboratory for discussions and revisions of the manuscript. Work in the Hajkova laboratory is supported by MRC funding (MC_US_A652_5PY70), the FP7 EpiGeneSys network and an ERC grant (ERC-CoG-648879–dynamicmodifications) to P.H. The laboratory of Y.Z. and S.P. is supported by grant 1R44GM096723-01A1. P.H. is a member of the EMBO Young Investigator Programme. P.W.S.H. is a recipient of an MRC PhD Studentship and MRC-targeted Doctoral Prize Fellowship from Imperial College London.
Extended data figures
This table contains GRR genes, E10 PGC gene FPKM values and differential expression in PGCs and mESCs.
This table shows differential methylation analysis in PGCs.
This table shows differential expression of transposable elements in Tet1-KO PGCs.