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X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner
Open accessAbstract
Embryogenesis requires the timely and coordinated activation of developmental regulators. It has been suggested that the recently discovered class of histone demethylases (UTX and JMJD3) that specifically target the repressive H3K27me3 modification play an important role in the activation of “bivalent” genes in response to specific developmental cues. To determine the requirements for UTX in pluripotency and development, we have generated Utx -null ES cells and mutant mice. The loss of UTX had a profound effect during embryogenesis. Utx -null embryos had reduced somite counts, neural tube closure defects and heart malformation that presented between E9.5 and E13.5. Unexpectedly, homozygous mutant female embryos were more severely affected than hemizygous mutant male embryos. In fact, we observed the survival of a subset of UTX-deficient males that were smaller in size and had reduced lifespan. Interestingly, these animals were fertile with normal spermatogenesis. Consistent with a midgestation lethality, UTX-null male and female ES cells gave rise to all three germ layers in teratoma assays, though sex-specific differences could be observed in the activation of developmental regulators in embryoid body assays. Lastly, ChIP-seq analysis revealed an increase in H3K27me3 in Utx -null male ES cells. In summary, our data demonstrate sex-specific requirements for this X-linked gene while suggesting a role for UTY during development.
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“In mice, loss of Utx is associated with severe developmental defects in females, but not males, and a shortened male lifespan (Welstead et al., 2012).”
From The Aging Epigenome (2016) · cites this paper as Welstead et al., 2012
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Benaissa, M. (2018) · theses.fr (ABES) · doi:10.70675/19229be6zcf7cz4317z80f0ze5bd9b22c989
Barbier, N. (2024) · theses.fr (ABES) · doi:10.70675/99c2b3c5z36bdz42fdz9878z99a368eb72e3
From chromatin dynamics to brain disease: Polycomb–Trithorax mechanisms in neurodevelopment
Castro, V. L., So, M. B., & Peng, J. C. (2026) · Trends in Neurosciences · doi:10.1016/j.tins.2026.06.001
Escape from X-chromosome inactivation: from gene discovery to regulatory mechanisms
Simoncini, C., & Loda, A. (2026) · Biochemical Society Transactions · doi:10.1042/bst20250104
BindingDB Entry 8054: Human UTY(KDM6C) is a male-specific Nϵ-methyl lysyl demethylase.
BindingDB (2017) · UC San Diego · doi:10.7270/q23x85j4
Metadata
- Authors
- Welstead, G. G., Creyghton, M. P., Bilodeau, S., Cheng, A. W., Markoulaki, S., Young, R. A., & Jaenisch, R.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-07-23
- Volume
- 109
- Issue
- 32
- Pages
- 13004-13009
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3420177
- OpenAlex
- W1985370709
- Cited by
- 194
- References
- 41
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 10 · 2023: 12 · 2022: 13 · 2021: 16 · 2020: 19 · 2019: 15 · 2018: 15 · 2017: 15 · 2016: 24 · 2015: 13 · 2014: 15 · 2013: 13 · 2012: 3
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
- Funders
- National Institutes of Health (HD 045022)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD045022, R37HD045022, 5-F32-F32HD055038, F32HD055038)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- 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
- Keywords
- KDM6A, H3K27me3 demethylase, embryonic development, X-linked genes, UTY, pluripotency, bivalent genes, neural tube closure, somitogenesis, cardiac anomalies, germ layer differentiation, teratoma, histone demethylation, JMJD3, embryoid body differentiation
- MeSH terms
- Animals, Female, Male, Mice, Mutant Strains, Sex Factors, Gene Expression Regulation, Developmental, Embryonic Development, Chromatin Immunoprecipitation, Mice, Embryonic Stem Cells, Gene Knockout Techniques, Histone Demethylases, Jumonji Domain-Containing Histone Demethylases
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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.
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