Summary Cell differentiation and function are regulated across multiple layers of gene regulation, including the modulation of gene expression by changes in chromatin accessibility. However, differentiation is an asynchronous process precluding a temporal understanding of the regulatory events leading to cell fate commitment. Here, we developed SHARE-seq, a highly scalable approach for measurement of chromatin accessibility and gene expression within the same single cell. Using 34,774 joint profiles from mouse skin, we develop a computational strategy to identify cis- regulatory interactions and define Domains of Regulatory Chromatin (DORCs), which significantly overlap with super-enhancers. We show that during lineage commitment, chromatin accessibility at DORCs precedes gene expression, suggesting changes in chromatin accessibility may prime cells for lineage commitment. We therefore develop a computational strategy (chromatin potential) to quantify chromatin lineage-priming and predict cell fate outcomes. Together, SHARE-seq provides an extensible platform to study regulatory circuitry across diverse cells within tissues.

Chromatin potential identified by shared single cell profiling of RNA and chromatin