Single-cell transcriptomes in the heart: when every epigenome counts

The response of an organ to stimuli emerges from the actions of individual cells. Recent cardiac single-cell RNA-sequencing studies of development, injury, and reprogramming have uncovered heterogeneous populations even among previously well-defined cell types, raising questions about what level of experimental resolution corresponds to disease-relevant, tissue-level phenotypes. In this review, we explore the biological meaning behind this cellular heterogeneity by undertaking an exhaustive analysis of single-cell transcriptomics in the heart (including a comprehensive, annotated compendium of studies published to date) and evaluating new models for the cardiac function that have emerged from these studies (including discussion and schematics that depict new hypotheses in the field). We evaluate the evidence to support the biological actions of newly identified cell populations and debate questions related to the role of cell-to-cell variability in development and disease. Finally, we present emerging epigenomic approaches that, when combined with single-cell RNA-sequencing, can resolve basic mechanisms of gene regulation and variability in cell phenotype.