Integrative single-cell chromatin and transcriptome profiling uncovers cell-type specific regulatory interactions

Simultaneous measurement of different molecular aspects of gene regulation can help infer functional relationships between genome regulation and gene expression, and understand their distinct and contribution to cell phenotype. Here, we present SHARE-seq, a highly scalable, sensitive, and cost-effective approach for joint measurement of chromatin accessibility and gene expression from the same single cells. Applying SHARE-seq to adult mouse tissues (skin, brain, lung) we show a direct congruence in cell type definition by either chromatin accessibility or RNA expression and create cell-type specific regulatory maps. We leverage naturally occurring cell-cell variation to infer chromatin-expression regulatory relationships and develop a broadly applicable computational strategy to define cis- ad trans- regulatory programs. The cis-regulatory programs, which largely overlap with super-enhancers, are found at key lineage-specifying genes. We demonstrate dynamic chromatin evidence of both gene expression lineage-priming and lineage-memory. The combined scalability and depth of SHARE-seq provide an extensible platform to study the regulatory relationships governing chromatin and gene expression changes across diverse cells within tissues. Overall design: SHARE-seq to profile chromatin accessibility and gene expression in the same cell from cell lines (GM12878, 3T3, K562, Raw 267.4), mouse skin, brain, and lung.