Cross-expression analysis reveals patterns of coordinated gene expression in spatial transcriptomics

Spatial transcriptomics promises to transform our understanding of tissue biology by molecularly profiling individual cells in situ. A fundamental question they allow us to ask is how nearby cells orchestrate their gene expression. To investigate this, we introduce cross-expression, a novel framework for discovering gene pairs that coordinate their expression across neighboring cells. Just as co-expression quantifies synchronized gene expression within the same cells, cross-expression measures coordinated gene expression between spatially adjacent cells, allowing us to understand tissue gene expression programs with single cell resolution. Using this framework, we recover ligand-receptor partners and discover gene combinations marking anatomical regions. More generally, we create cross-expression networks to find gene modules with orchestrated expression patterns. Finally, we provide an efficient R package to facilitate cross-expression analysis, quantify effect sizes, and generate novel visualizations to better understand spatial gene expression programs.