Single-cell microRNA/mRNA co-sequencing reveals non-genetic heterogeneity and novel regulatory mechanisms

Co-measurement of multiple omic profiles from the same single cells opens up the opportunity to decode molecular regulation that underlie intercellular heterogeneity in development and disease. This method demonstrates good robustness and reproducibility for detecting both microRNAs and mRNAs in single cells, and yields paired half-cell microRNA and mRNA profiles that could be independently validated. Here, we present co-sequencing of microRNAs and mRNAs in the same single cells using a half-cell genomics approach. Linking the level of miRNAs to the expression of predicted target mRNAs across 19 single cells that are phenotypically identical, we observe that the predicted targets are significantly anti-correlated with the variation of abundantly expressed miRNAs, suggesting that miRNA expression variability alone may lead to non-genetic cell-to-cell heterogeneity. Genome scale analysis of paired miRNA-mRNA co-profiles further allows us to derive and validate new regulatory relationships of cellular pathways controlling miRNA expression and variability.