Related Experiment Video
Updated: Jun 16, 2025
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Combined DNA-RNA Fluorescent In situ Hybridization FISH to Study X Chromosome Inactivation in Differentiated Female Mouse Embryonic Stem Cells
Published on: June 14, 2014
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Ubinuclein 2 is essential for mouse development and functions in X chromosome inactivation
Asun Monfort1, Giulio Di Minin1, Sarah Sting1
1Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland.
Plos Genetics
|June 2, 2025
Summary
The HIRA complex is crucial for gene regulation in mice, particularly in female X-chromosome inactivation. Mutations in Ubn1 and Ubn2 genes disrupt this process, leading to developmental issues and impacting gene silencing.
Area of Science:
- Epigenetics
- Developmental Biology
- Genetics
Background:
- The Histone Regulator A (HIRA) complex deposits histone H3.3 independently of DNA replication.
- The precise role of the HIRA complex in gene regulation, especially during mammalian development, requires further elucidation.
- Understanding the HIRA complex's function is key to comprehending epigenetic mechanisms governing gene expression.
Purpose of the Study:
- To investigate the in vivo functions of the HIRA complex, specifically the genes Ubn1 and Ubn2, in mouse development and gene regulation.
- To determine the mechanistic link between HIRA complex function and X-chromosome inactivation.
- To identify the earliest molecular events affected by HIRA complex mutations during X inactivation initiation.
Main Methods:
- Analysis of Ubn1 and Ubn2 gene mutations in mice, including viability, fertility, and embryonic development assessments.
- Examination of combined Ubn1 and Ubn2 mutations to assess synergistic effects on embryonic lethality and development.
- Molecular analysis of mouse embryonic stem cells with mutations in Ubn1, Ubn2, and Hira to study X inactivation initiation and Xist-mediated gene silencing.
Main Results:
- Ubn1 mutant mice are viable and fertile, while Ubn2 mutations cause embryonic lethality with a male-biased sex ratio.
- Combined Ubn1 and Ubn2 mutations lead to complete embryonic lethality and developmental arrest, with a notable reduction in female embryos.
- Mutations in Ubn1, Ubn2, and Hira impair Xist-mediated gene silencing, with the earliest defect being the failure to establish histone H3 tri-methylation on X-linked genes.
Conclusions:
- The HIRA complex plays a critical, sex-specific role in the initiation of X-chromosome inactivation in female mice.
- Loss of Ubinucleins (Ubn1/Ubn2) disrupts the normal epigenetic switch from histone H3 acetylation to tri-methylation on X-linked genes during X inactivation.
- These findings reveal a novel function of the HIRA complex in establishing repressive histone marks essential for developmental gene silencing.
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