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

To understand epigenetic inheritance in mammals, we investigate cell division modes and histone inheritance patterns in the mouse olfactory epithelium using an injury-induced regeneration model. Horizontal basal cells (HBCs), the adult stem cells in this tissue, undergo asymmetric division, coinciding with asymmetric histone H4 inheritance in vivo. Primary HBCs recapitulate both asymmetric cell division and asymmetric histone inheritance for H4, H3, and H3.3, but not H2A-H2B. Upon mitotic exit, asymmetric histone inheritance correlates with differential enrichment of a key 'stemness' transcription factor p63 and asynchronous transcription re-initiation. Single-cell RNA sequencing of paired daughter cells reveals their asymmetric cell fate priming in this multilineage stem cell system. Furthermore, disruption of asymmetric cell division abolishes these asymmetric cellular features, impairing olfactory epithelium regeneration and smell behavior in mice. Together, these findings reveal asymmetric histone inheritance in a mammalian adult stem cell lineage and highlight its biological significance in tissue regeneration and animal behavior.