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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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  • 14 March 2018

    The received date was corrected in the HTML from 21 July 2015 to 21 July 2017.


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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.

Author information

Author notes

    • Hakan Bagci
    •  & Vanja Haberle

    Present addresses: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr Bohr-Gasse 7, 1030 Vienna, Austria (V.H.); Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK (H.B.).

    • Harry G. Leitch
    • , Cristina E. Requena
    • , Zhiyi Sun
    •  & Rachel Amouroux

    These authors contributed equally to this work.


  1. MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK

    • Peter W. S. Hill
    • , Harry G. Leitch
    • , Cristina E. Requena
    • , Rachel Amouroux
    • , Monica Roman-Trufero
    • , Malgorzata Borkowska
    • , Sarah Linnett
    • , Hakan Bagci
    • , Gopuraja Dharmalingham
    • , Vanja Haberle
    • , Boris Lenhard
    •  & Petra Hajkova
  2. Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK

    • Peter W. S. Hill
    • , Harry G. Leitch
    • , Cristina E. Requena
    • , Rachel Amouroux
    • , Monica Roman-Trufero
    • , Malgorzata Borkowska
    • , Sarah Linnett
    • , Hakan Bagci
    • , Gopuraja Dharmalingham
    • , Vanja Haberle
    • , Boris Lenhard
    •  & Petra Hajkova
  3. New England Biolabs, Inc., 240 County Road, Ipswich, Massachusetts 01938, USA

    • Zhiyi Sun
    • , Jolyon Terragni
    • , Romualdas Vaisvila
    • , Yu Zheng
    •  & Sriharsa Pradhan


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P.H. and P.W.S.H. conceived the study; P.W.S.H. performed the experiments and analysed the data; H.G.L. carried out mouse ES cell experiments with the help of M.B. and M.R.-T.; C.E.R. generated Tet1−/− DNMT TKO mouse ES cell line with the help of H.B.; R.A. carried out LC–MS/MS experiments and analysed the data with the help of S.L.; J.T. made Aba–seq libraries with support from Y.Z.; computational analysis was carried out by P.W.S.H. with the help of Z.S., G.D., V.H., and B.L.; R.V. performed experiments; P.W.S.H. and P.H. wrote the manuscript with assistance from S.P. and B.L.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Petra Hajkova.

Reviewer Information Nature thanks Y. Matsui and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

  2. 2.

    Supplementary Information

    This file contains Supplementary Tables 1-6, Supplementary Figure 1 and Supplementary References.

Excel files

  1. 1.

    Supplementary Table 7

    This table contains GRR genes, E10 PGC gene FPKM values and differential expression in PGCs and mESCs.

  2. 2.

    Supplementary Table 8

    This table shows differential methylation analysis in PGCs.

  3. 3.

    Supplementary Table 9

    This table shows differential expression of transposable elements in Tet1-KO PGCs.

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