Joint single-cell multiomic analysis in Wnt3a induced asymmetric stem cell division.

Wnt signaling usually functions through a spatial gradient. Localized Wnt3a signaling can induce the asymmetric division of mouse embryonic stem cells, where proximal daughter cells maintain self-renewal and distal daughter cells acquire hallmarks of differentiation. Here, we develop an approach, same cell epigenome and transcriptome sequencing, to jointly profile the epigenome and transcriptome in the same single cell. Utilizing this method, we profiled H3K27me3 and H3K4me3 levels along with gene expression in mouse embryonic stem cells with localized Wnt3a signaling, revealing the cell type-specific maps of the epigenome and transcriptome in divided daughter cells. H3K27me3, but not H3K4me3, is correlated with gene expression changes during asymmetric cell division. Furthermore, cell clusters identified by H3K27me3 recapitulate the corresponding clusters defined by gene expression. Our study provides a convenient method to jointly profile the epigenome and transcriptome in the same cell and reveals mechanistic insights into the gene regulatory programs that maintain and reset stem cell fate during differentiation.