Asymmetric Histone Inheritance Regulates Differential Transcription Re-initiation and Cell Fate Decisions in Mouse Olfactory Horizontal Basal Cells

Histones, major carriers of epigenetic information, play critical roles in regulating gene expression patterns and cell fate decisions. While asymmetric histone inheritance has been shown to regulate distinct cell fates in Drosophila adult stem cells, its relevance in mammals remains unclear. In this study, we investigated cell division modes and histone inheritance patterns in horizontal basal cells (HBCs) of the mouse olfactory epithelium following injury. We found that approximately 40% of telophase HBCs show asymmetric division, with a corresponding asymmetric segregation of histone H4. In primary cultured HBCs, we observed asymmetric cell division accompanied by asymmetric distribution of histones, including H4, H3, and H3.3, but not H2A-H2B. Asymmetric histone segregation leads to asymmetric association of a key ‘stemness’ transcription factor p63 and asynchronous transcription re-initiation during mitotic exit. Single-cell RNA sequencing of paired daughter cells further revealed asymmetric cell fate priming in cultured HBCs. Disruption of asymmetric cell division abolished asymmetric transcription re-initiation, asymmetric histone inheritance in culture HBCs and further caused regeneration defects in OE. These findings reveal the conservation of asymmetric histone inheritance in mammalian adult stem cells and highlight its biological significance in tissue regeneration.