Tet1 and Tet2 Regulate 5-Hydroxymethylcytosine Production and Cell Lineage Specification in Mouse Embryonic Stem Cells
Open accessAbstract
TET family enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. Here, we show that Tet1 and Tet2 are Oct4-regulated enzymes that together sustain 5hmC in mouse embryonic stem cells (ESCs) and are induced concomitantly with 5hmC during reprogramming of fibroblasts to induced pluripotent stem cells. ESCs depleted of Tet1 by RNAi show diminished expression of the Nodal antagonist Lefty1 and display hyperactive Nodal signaling and skewed differentiation into the endoderm-mesoderm lineage in embryoid bodies in vitro. In Fgf4- and heparin-supplemented culture conditions, Tet1-depleted ESCs activate the trophoblast stem cell lineage determinant Elf5 and can colonize the placenta in midgestation embryo chimeras. Consistent with these findings, Tet1-depleted ESCs form aggressive hemorrhagic teratomas with increased endoderm, reduced neuroectoderm, and ectopic appearance of trophoblastic giant cells. Thus, 5hmC is an epigenetic modification associated with the pluripotent state, and Tet1 functions to regulate the lineage differentiation potential of ESCs.
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Tet1 and Tet2, but not Tet3, were upregulated by OSK.
“Because Tet1 and Tet2, but not Tet3, were upregulated by OSK35,36 (Extended Data Fig. 6a), we tested the effect of knocking down Tet1 or Tet2 (sh-Tet1 or sh-Tet2) using AAV37 in the context of damaged, OSK-treated RGCs (Extended Data Fig. 6b–d).”
From Reprogramming to recover youthful epigenetic information and restore vision (2020) · cites this paper as [35]
The Results section reports that Tet1 and Tet2 expression increased, while Tet3 expression decreased, when mouse fibroblasts were reprogrammed to iPS cells. However, the paper used Oct4, Sox2, Klf4 and c-Myc (OSKM), not OSK alone, so it does not establish the claimed response to OSK. (LLM, conf=0.87)
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Jaffer, S., Goh, P., Abbasian, M., & Nathwani, A. C. (2018) · International Journal of Stem Cells · doi:10.15283/ijsc18036 · Cited by 9 · see citing works
- Authors
- Koh, K. P., Yabuuchi, A., Rao, S., Huang, Y., Cunniff, K., Nardone, J., Laiho, A., Tahiliani, M., Sommer, C. A., Mostoslavsky, G., Lahesmaa, R., Orkin, S. H., Rodig, S. J., Daley, G. Q., & Rao, A.
- Affiliations
- Boston Children's Hospital (US)
- Cell Signaling Technology (United States) (US)
- Åbo Akademi University (FI)
- Boston University (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Rao, Anjana
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2011-02
- Volume
- 8
- Issue
- 2
- Pages
- 200-213
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC3134318
- OpenAlex
- W2138472595
- Cited by
- 776
- References
- 49
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 22 · 2023: 37 · 2022: 37 · 2021: 34 · 2020: 31 · 2019: 54 · 2018: 52 · 2017: 47 · 2016: 55 · 2015: 48 · 2014: 77 · 2013: 96 · 2012: 88
- FWCI
- 41.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lirias (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Heart, Lung, and Blood Institute (UO1‑HL100001, U01HL100001, RC2HL102815)
- National Institute on Drug Abuse (RC1DA028422)
- National Cancer Institute (CA-42471, R01CA042471, R37CA042471)
- National Institute of Allergy and Infectious Diseases (AI44432, R01AI044432)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK059279, R01DK070055)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD065812)
- 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 › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- TET1, TET2, 5-hydroxymethylcytosine, mouse embryonic stem cells, Oct4, Nodal signaling, Lefty1, ELF5, teratoma, induced pluripotent stem cells, fibroblast reprogramming, cell lineage specification
- MeSH terms
- Animals, Binding Sites, Cell Differentiation, Cytosine, DNA-Binding Proteins, Proto-Oncogene Proteins, Teratoma, Cell Lineage, Computational Biology, 5-Methylcytosine, Chromatin Immunoprecipitation, Dioxygenases, Octamer Transcription Factor-3, Mice, Embryonic Stem Cells
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