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NANOG alone induces germ cells in primed epiblast in vitro by activation of enhancers
Open accessAbstract
Nanog, a core pluripotency factor in the inner cell mass of blastocysts, is also expressed in unipotent primordial germ cells (PGCs) in mice, where its precise role is yet unclear. We investigated this in an in vitro model, in which naive pluripotent embryonic stem (ES) cells cultured in basic fibroblast growth factor (bFGF) and activin A develop as epiblast-like cells (EpiLCs) and gain competence for a PGC-like fate. Consequently, bone morphogenetic protein 4 (BMP4), or ectopic expression of key germline transcription factors Prdm1, Prdm14 and Tfap2c, directly induce PGC-like cells (PGCLCs) in EpiLCs, but not in ES cells. Here we report an unexpected discovery that Nanog alone can induce PGCLCs in EpiLCs, independently of BMP4. We propose that after the dissolution of the naive ES-cell pluripotency network during establishment of EpiLCs, the epigenome is reset for cell fate determination. Indeed, we found genome-wide changes in NANOG-binding patterns between ES cells and EpiLCs, indicating epigenetic resetting of regulatory elements. Accordingly, we show that NANOG can bind and activate enhancers of Prdm1 and Prdm14 in EpiLCs in vitro; BLIMP1 (encoded by Prdm1) then directly induces Tfap2c. Furthermore, while SOX2 and NANOG promote the pluripotent state in ES cells, they show contrasting roles in EpiLCs, as Sox2 specifically represses PGCLC induction by Nanog. This study demonstrates a broadly applicable mechanistic principle for how cells acquire competence for cell fate determination, resulting in the context-dependent roles of key transcription factors during development.
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“For Dex inducible WT or APPA Mettl3 plasmid, GRBD insert from pPyCAG-cGR-IP plasmid (RIKEN, #RDB10440) was subcloned to constitutive PiggyBac plasmid to generate GRBD-FLAG-METTL3WT or GRBD-FLAG-METTL3APPA fusion protein (Murakami et al., 2016).”
From METTL3 uncouples chromatin accessibility from transcription during retinal development (2025) · cites this paper as Murakami et al., 2016
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BackgroundSpecification and epigenetic programming of the human germ line
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Metadata
- Authors
- Murakami, K., Günesdogan, U., Zylicz, J. J., Tang, W. W. C., Sengupta, R., Kobayashi, T., Kim, S., Butler, R., Dietmann, S., & Azim Surani, M.
- Affiliations
- Hokkaido University (JP)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- ORCID
- Venue
- Nature
- Published
- 2016-01
- Volume
- 529
- Issue
- 7586
- Pages
- 403-407
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4724940
- OpenAlex
- W2238949050
- Cited by
- 180
- References
- 40
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 12 · 2023: 15 · 2022: 19 · 2021: 28 · 2020: 15 · 2019: 26 · 2018: 22 · 2017: 17 · 2016: 11
- FWCI
- 13.17
- 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)
- Apollo (University of Cambridge) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Wellcome Trust (RG44593, 096738, 092096)
- Cancer Research UK (C6946 /A14492)
- Medical Research Council (MC_PC_12009)
- Japan Society for the Promotion of Science (15K18539)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- Nanog, epiblast-like cells, enhancer activation, chromatin accessibility, Blimp-1, PRDM14, TFAP2C, SOX2, pluripotency, naïve-to-primed transition, transcription factor binding sites
- MeSH terms
- Mouse Embryonic Stem Cells, Nanog Homeobox Protein, Positive Regulatory Domain I-Binding Factor 1, Animals, Cell Differentiation, Chromatin, DNA-Binding Proteins, Enhancer Elements, Genetic, Female, Germ Cells, Germ Layers, Male, Protein Binding, Transcription Factors, Fibroblast Growth Factor 2, RNA-Binding Proteins, Genome, Homeodomain Proteins, Gene Expression Regulation, Developmental, Activins, Pluripotent Stem Cells, Epigenesis, Genetic, Transcription Factor AP-2, Mice, Bone Morphogenetic Protein 4, SOXB1 Transcription Factors
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