Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis
Open accessAbstract
Significance: Development of preimplantation embryos entails global DNA demethylation on the zygotic genome. The original thought was that TET-deficient embryos would be unlikely to survive early embryogenesis because they would be unable to mediate genome-wide demethylation in the zygote and preimplantation embryo. However, mice lacking the individual TET proteins Tet1, Tet2, or Tet3 have survived until birth and beyond, suggesting redundancy among TET proteins in the early embryogenesis. Here we report that preimplantation embryos doubly disrupted for Tet1 and Tet3 show abnormal embryonic phenotypes, whose incomplete penetrance correlates with a high variability of transcriptional profiles and DNA methylation status. Our data suggest that in addition to facilitating DNA demethylation, TET proteins and oxidized methylcytosines may regulate the consistency of gene transcription during embryogenesis.
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Loss of Tet1 impairs periportal identity and function and represses pericentral characteristics regulated through Hedgehog signalling.
“Developmentally, Tet1 deletion impairs periportal identity and function, while repressing the pericentral characteristics regulated through Hedgehog signalling2,14.”
From Multi-zonal liver organoids from human pluripotent stem cells (2025) · cites this paper as [2]
The Discussion (p. 9) reports down-regulation of Hedgehog-signaling genes in Tet1/Tet3 double-knockout blastocysts, and the results (p. 8) report reduced Hedgehog-pathway components in later embryos. The paper does not establish that Tet1 deletion alone impairs periportal identity or function, or that it represses pericentral characteristics. (LLM, conf=0.86)
Experimental — accuracy not yet measuredZonal liver architecture has not yet been replicated in vitro.
“zonal liver architecture has not yet been replicated in vitro2,3.”
From Multi-zonal liver organoids from human pluripotent stem cells (2025) · cites this paper as [2]
The early-development passages (pp. 3–4) concern Tet1/3-deficient embryos and transcriptome variability, not liver architecture. Searches for zonal liver architecture and in vitro liver zonation found no passage addressing whether it has been replicated. (LLM, conf=0.77)
Experimental — accuracy not yet measuredWhen mZ-HLOs are treated with inhibitors targeting HIF1A and TET1, zonal identities are lost.
“Following such developmental patterns, mZ-HLOs exposed to inhibitors specific to HIF1A and TET1 lead to the loss of zonal identities2,14.”
From Multi-zonal liver organoids from human pluripotent stem cells (2025) · cites this paper as [2]
The Significance section (p. 2) reports increased transcriptome variability in mouse embryos lacking Tet1 and Tet3, not inhibitor-treated mZ-HLOs. The Discussion (pp. 8–9) addresses TET loss of function but does not report HIF1A inhibition or loss of zonal identities. Searches for mZ-HLOs, HIF1A inhibitors, liver organoids, and zonation found no passage addressing the claimed result. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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- Authors
- Kang, J., Lienhard, M., Pastor, W. A., Chawla, A., Novotny, M., Tsagaratou, A., Lasken, R. S., Thompson, E. C., Surani, M. A., Koralov, S. B., Kalantry, S., Chavez, L., & Rao, A.
- Affiliations
- La Jolla Institute for Immunology (US)
- J. Craig Venter Institute (US)
- University of Cambridge (GB)
- NYU Langone Health (US)
- University of Michigan (US)
- Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, CA 92037;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-07-21
- Volume
- 112
- Issue
- 31
- Pages
- E4236-45
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4534209
- OpenAlex
- W2152478160
- Cited by
- 126
- References
- 76
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 15 · 2023: 8 · 2022: 8 · 2021: 19 · 2020: 9 · 2019: 10 · 2018: 10 · 2017: 8 · 2016: 15 · 2015: 3
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (acceptedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (AI044432)
- HHS | NIH | National Institute of Child Health and Human Development (5R01HD065812)
- HHS | NIH | Office of Strategic Coordination (DP2-OD-008646-01)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- TET1, TET3, TET enzymes, DNA demethylation, 5-hydroxymethylcytosine, 5-methylcytosine, transcriptional noise, early embryonic development, blastocyst, holoprosencephaly, cholesterol biosynthesis, repetitive elements, epigenetic regulation
- MeSH terms
- Animals, Blastocyst, Blastomeres, Cholesterol, DNA, DNA-Binding Proteins, Embryo, Mammalian, Mice, Inbred C57BL, Proto-Oncogene Proteins, Repetitive Sequences, Nucleic Acid, Signal Transduction, Biomarkers, Down-Regulation, Gene Deletion, Sequence Analysis, RNA, Mice, Knockout, Genomic Imprinting, Gene Expression Regulation, Developmental, Cell Lineage, Embryo Loss, 5-Methylcytosine, Embryonic Development, Dioxygenases, Hedgehog Proteins, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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