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A knockout-first model of H3f3a gene targeting leads to developmental lethality
Kelly Bush1,2,3, Vanessa Cervantes1,2,3, Jennifer Q Yee1,2,3
1Department of Cell Biology and Human Anatomy, University of California Davis, Davis, California, USA.
The H3f3a gene knockout in mice results in embryonic lethality with developmental defects. This highlights the critical, cell-type-specific roles of histone variant H3.3 in development.
Area of Science:
- Epigenetics
- Developmental Biology
- Genetics
Background:
- Histone variant H3.3 is crucial for development, encoded by H3f3a and H3f3b genes with differential expression.
- Previous studies show H3f3b knockout causes lethality and infertility, but the specific role of H3f3a requires further investigation.
Purpose of the Study:
- To investigate the developmental role of the H3f3a gene using a knockout-first approach in C57BL6 mice.
Main Methods:
- Utilized a knockout-first strategy to inactivate the H3f3a gene in mice.
- Analyzed embryonic morphology, protein levels (H3.3, total H3), histone modifications, and gene expression in H3f3a nulls.
Main Results:
- Homozygous H3f3a knockout led to embryonic lethality at or before birth.
- Null embryos exhibited morphological defects, including reduced size and smaller head/brain size.
- Increased phospho-Serine31 (a H3.3 mark) and altered protocadherin gene expression were observed in H3f3a null neurospheres.
Conclusions:
- H3f3a plays an essential role in embryonic development, with its loss causing severe defects and lethality.
- Findings support differential and cell-type-specific functions of H3f3a and H3f3b in H3.3-mediated epigenetic regulation and development.
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