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Cited by 80Pluripotent Stem Cells ResearchEpigenetics and DNA MethylationAnimal Genetics and Reproduction

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In vitro reconstitution of epigenetic reprogramming in the human germ line

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Murase, Yusuke, Yokogawa, Ryuta, Yabuta, Yukihiro, Nagano, Masahiro, Katou, Yoshitaka, Mizuyama, Manami, Kitamura, Ayaka, Puangsricharoen, Pimpitcha, Yamashiro, Chika, Hu, Bo, Mizuta, Ken, Tsujimura, Taro, Yamamoto, Takuya, Ogata, Kosuke, Ishihama, Yasushi, Saitou, Mitinori·2024·Nature
DOI 10.1038/s41586-024-07526-6PMC PMC11222161
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Abstract

Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia. This process ensures sexually dimorphic germ cell development for totipotency 1 . In vitro reconstitution of epigenetic reprogramming in humans remains a fundamental challenge. Here we establish a strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem-cell-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (about >10 10 -fold). Bone morphogenetic protein (BMP) signalling is a key driver of these processes. BMP-driven hPGCLC differentiation involves attenuation of the MAPK (ERK) pathway and both de novo and maintenance DNA methyltransferase activities, which probably promote replication-coupled, passive DNA demethylation. hPGCLCs deficient in TET1, an active DNA demethylase abundant in human germ cells 2,3 , differentiate into extraembryonic cells, including amnion, with de-repression of key genes that bear bivalent promoters. These cells fail to fully activate genes vital for spermatogenesis and oogenesis, and their promoters remain methylated. Our study provides a framework for epigenetic reprogramming in humans and an important advance in human biology. Through the generation of abundant mitotic pro-spermatogonia and oogonia-like cells, our results also represent a milestone for human in vitro gametogenesis research and its potential translation into reproductive medicine.

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  • Germline transmission of trauma-related effects may involve a combination of incomplete epigenetic erasure and RNA-mediated signaling mechanisms.

    “Such findings suggest that germline transmission of trauma-related effects may involve a combination of incomplete epigenetic erasure and RNA-mediated signaling mechanisms, offering a biologically plausible framework despite extensive reprogramming.”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [140]

    The DNA methylome reprogramming section (page not provided) reports that some regions escape demethylation, supporting the possibility of incomplete epigenetic erasure in the studied human germ-cell model. It does not connect those escapees to trauma-related germline transmission or describe RNA-mediated signaling as a mechanism for such transmission. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Certain genomic regions, including imprinted loci, non-imprinted loci, and retrotransposable elements, may partially escape complete demethylation.

    “Certain genomic regions, including imprinted loci, non-imprinted loci, and retrotransposable elements, may partially escape complete demethylation (139, 140).”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [140]

  • Accumulating evidence suggests that epigenetic reprogramming is not absolute.

    “However, accumulating evidence suggests that epigenetic reprogramming is not absolute.”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [140]

  • Experimental studies demonstrate that sperm-derived small noncoding RNAs, including miRNAs, tsRNAs, and lncRNA, can transmit information about paternal stress exposure independently of stable DNA methylation changes.

    “In addition, experimental studies demonstrate that sperm-derived small noncoding RNAs, including miRNAs, tsRNAs, and lncRNA, can transmit information about paternal stress exposure independently of stable DNA methylation changes (139, 140).”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [140]

    The DNA methylome reprogramming section (page not provided) examines DNA methylation during differentiation of human germ cells, not transmission of paternal stress. Searches for sperm-derived small RNAs and paternal-stress inheritance found no passage addressing the claimed RNA mechanism or its independence from stable DNA methylation changes. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • These RNA-mediated pathways influence neurodevelopmental, metabolic, and stress-related phenotypes in offspring in animal models.

    “These RNA-mediated pathways influence neurodevelopmental, metabolic, and stress-related phenotypes in offspring in animal models.”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [140]

    The Transcriptome dynamics and TET1 prevents aberrant differentiation sections discuss RNA-seq and maturation of human germ-cell-like cells, not RNA-mediated effects on offspring. Searches for offspring phenotypes and neurodevelopmental, metabolic, or stress-related outcomes in animal models found no passage addressing the claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Metadata

Authors
Murase, Y., Yokogawa, R., Yabuta, Y., Nagano, M., Katou, Y., Mizuyama, M., Kitamura, A., Puangsricharoen, P., Yamashiro, C., Hu, B., Mizuta, K., Tsujimura, T., Yamamoto, T., Ogata, K., Ishihama, Y., & Saitou, M.
Affiliations
Kyoto University (JP)
Corresponding author
Saitou, Mitinori
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2024-05-20
Volume
631
Issue
8019
Pages
170-178
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-024-07526-6
PMC
PMC11222161
OpenAlex
W4398145535
Cited by
80
References
7
Citations by year
2026: 32 · 2025: 36 · 2024: 12
FWCI
10.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
Japan Society for the Promotion of Science (17H06098)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Animal Genetics and Reproduction
Keywords
epigenetic reprogramming, primordial germ cells, oogonia, in vitro gametogenesis, BMP signaling, MAPK/ERK pathway, DNA demethylation, DNA methyltransferases, TET1, bivalent promoters, extraembryonic cells, amniotic membrane, spermatogenesis, oogenesis, totipotency
MeSH terms
Amnion, Cell Differentiation, DNA-Binding Proteins, Female, Germ Cells, Humans, Mixed Function Oxygenases, Male, Mitosis, Oogenesis, Oogonia, Promoter Regions, Genetic, Proto-Oncogene Proteins, Spermatogenesis, Spermatogonia, Gene Expression Regulation, Developmental, DNA Methylation, Bone Morphogenetic Proteins, MAP Kinase Signaling System, Pluripotent Stem Cells, Epigenesis, Genetic, Cellular Reprogramming, In Vitro Techniques

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