Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte
Open accessAbstract
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). Following subsequent migration into the developing gonad, PGCs undergo a wave of extensive epigenetic reprogramming around E10.5-E11.5, including genome-wide loss of 5-methylcytosine. The underlying molecular mechanisms of this process have remained unclear, leading to our inability to recapitulate this step of germline development in vitro. 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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Global erasure of DNA methylation in primordial germ cells does not cause widespread transcriptional activation.
“For example, global erasure of DNA methylation in primordial germ cells (PGCs) does not lead to widespread transcriptional activation (16, 17)”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [17]
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- Authors
- Hill, P. W. S., Leitch, H. G., Requena, C. E., Sun, Z., Amouroux, R., Roman-Trufero, M., Borkowska, M., Terragni, J., Vaisvila, R., Linnett, S., Bagci, H., Dharmalingham, G., Haberle, V., Lenhard, B., Zheng, Y., Pradhan, S., & Hajkova, P.
- Affiliations
- MRC London Institute of Medical Sciences (GB)
- New England Biolabs (United States) (US)
- ORCID
- Venue
- Nature
- Published
- 2018-03
- Volume
- 555
- Issue
- 7696
- Pages
- 392-396
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5856367
- OpenAlex
- W2789804929
- Cited by
- 272
- References
- 40
- Citations by year
- 2026: 18 · 2025: 28 · 2024: 22 · 2023: 29 · 2022: 43 · 2021: 55 · 2020: 28 · 2019: 35 · 2018: 14
- FWCI
- 11.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- National Institute for Health and Care Research (ACF-2016-21-501)
- National Institute of General Medical Sciences (R44GM096723)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- primordial germ cells, epigenetic reprogramming, DNA demethylation, TET1, PRC1, gametogenesis, meiosis, germ cell development, in vitro gametogenesis
- MeSH terms
- Animals, DNA-Binding Proteins, Female, Gametogenesis, Germ Cells, Male, Meiosis, Proto-Oncogene Proteins, DNA Methylation, Epigenesis, Genetic, 5-Methylcytosine, Mice, Cellular Reprogramming
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