Naive pluripotency is associated with global DNA hypomethylation
Open accessAbstract
Naive pluripotent embryonic stem cells (ESCs) and embryonic germ cells (EGCs) are derived from the preimplantation epiblast and primordial germ cells (PGCs), respectively. We investigated whether differences exist between ESCs and EGCs, in view of their distinct developmental origins. PGCs are programmed to undergo global DNA demethylation; however, we find that EGCs and ESCs exhibit equivalent global DNA methylation levels. Inhibition of MEK and Gsk3b by 2i conditions leads to pronounced reduction in DNA methylation in both cell types. This is driven by Prdm14 and is associated with downregulation of Dnmt3a and Dnmt3b. However, genomic imprints are maintained in 2i, and we report derivation of EGCs with intact genomic imprints. Collectively, our findings establish that culture in 2i instills a naive pluripotent state with a distinctive epigenetic configuration that parallels molecular features observed in both the preimplantation epiblast and nascent PGCs.
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Naïve mouse ESCs accumulate pools of αKG and acetyl-CoA, which may reinforce the pluripotent state by stimulating more open chromatin.
“Moreover, naïve mouse ESCs accumulate pools of αKG and acetyl-CoA, which may reinforce the pluripotent state by stimulating more open chromatin (165, 211, 212, 213, 214).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [211]
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- Authors
- Leitch, H. G., McEwen, K. R., Turp, A., Encheva, V., Carroll, T., Grabole, N., Mansfield, W., Nashun, B., Knezovich, J. G., Smith, A., Surani, M. A., & Hajkova, P.
- Affiliations
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Imperial College London (GB)
- University of Cambridge (GB)
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2013-02-17
- Volume
- 20
- Issue
- 3
- Pages
- 311-316
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC3591483
- OpenAlex
- W2053056178
- Cited by
- 516
- References
- 58
- Citations by year
- 2026: 12 · 2025: 25 · 2024: 24 · 2023: 27 · 2022: 29 · 2021: 32 · 2020: 58 · 2019: 41 · 2018: 41 · 2017: 58 · 2016: 47 · 2015: 46 · 2014: 50 · 2013: 24
- FWCI
- 24.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (079249, RG49135, 092096, 96738)
- Medical Research Council (MC_PC_12009)
- 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 › Genetic Syndromes and Imprinting
- Keywords
- naive pluripotency, DNA hypomethylation, embryonic stem cells, embryonic germ cells, primordial germ cells, global DNA methylation, genomic imprinting, MEK inhibition, PRDM14, DNMT3A, DNMT3B, epigenetic reprogramming
- MeSH terms
- Glycogen Synthase Kinase 3 beta, DNA Methyltransferase 3A, DNA Methyltransferase 3B, Animals, Benzamides, Cell Differentiation, Cells, Cultured, Diphenylamine, DNA (Cytosine-5-)-Methyltransferases, DNA-Binding Proteins, Enzyme Inhibitors, Germ Cells, Germ Layers, Mice, Inbred C57BL, Pyridines, Pyrimidines, Transcription Factors, RNA-Binding Proteins, Genomic Imprinting, DNA Methylation, Gene Expression Profiling, MAP Kinase Kinase Kinases, Glycogen Synthase Kinase 3, Pluripotent Stem Cells, Epigenesis, Genetic, Mice, Embryonic Stem Cells, Transcriptome
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