Abstract

Co‐expression of two or more genes at the single‐cell level is usually associated with functional co‐regulation. While mRNA co‐expression—measured as the correlation in mRNA levels—can be influenced by both transcriptional and post‐transcriptional events, transcriptional regulation is typically considered dominant. We review and connect the literature describing transcriptional and post‐transcriptional regulation of co‐expression. To enhance our understanding, we integrate four datasets spanning single‐cell gene expression data, single‐cell promoter activity data and individual transcript half‐lives. Confirming expectations, we find that positive co‐expression necessitates promoter coordination and similar mRNA half‐lives. Surprisingly, negative co‐expression is favored by differences in mRNA half‐lives, contrary to initial predictions from stochastic simulations. Notably, this association manifests specifically within clusters of genes. We further observe a striking compensation between promoter coordination and mRNA half‐lives, which additional stochastic simulations suggest might give rise to the observed co‐expression patterns. These findings raise intriguing questions about the functional advantages conferred by this compensation between distal kinetic steps.