Single cell RNA-seq and ATAC-seq indicate critical roles of Isl1 and Nkx2-5 for cardiac progenitor cell transition states and lineage settlement

SUMMARY Formation and segregation of cell lineages building the vertebrate heart have been studied extensively by genetic cell tracing techniques and by analysis of single marker gene expression but the underlying gene regulatory networks driving cell fate transitions during early cardiogenesis are only partially understood. Here, we comprehensively characterized mouse cardiac progenitor cells (CPC) marked by Nkx2-5 and Isl1 expression from E7.5 to E9.5 using single-cell RNA sequencing. By leveraging on cell-to-cell heterogeneity, we identified different previously unknown cardiac sub-populations. Reconstruction of the developmental trajectory revealed that Isl1 + CPC represent a transitional cell population maintaining a prolonged multipotent state, whereas extended expression of Nkx2-5 commits CPC to a unidirectional cardiomyocyte fate. Furthermore, we show that CPC fate transitions are associated with distinct open chromatin states, which critically depend on Isl1 and Nkx2-5. Our data provide a model of transcriptional and epigenetic regulations during cardiac progenitor cell fate decisions at single-cell resolution.