Single-cell roadmap of cardiac differentiation identifies roles for ZNF711 and retinoic acid in balanced epicardial and cardiomyocyte lineage commitment

Stem cell-based models of human heart tissue and cardiac differentiation employ monolayer and 3D organoid cultures with different properties, cell type composition, and maturity. We constructed a single-cell roadmap of atrial and ventricular differentiation conditions, enabling direct comparisons of monolayer, cardiac embryoid body, and engineered heart tissue trajectories. Using a multiomic approach and gene-regulatory network inference, we focused on the regulators of the epicardial, atrial and ventricular cardiomyocyte lineages. We identified ZNF711 as a regulatory switch and safe-guard for cardiomyocyte commitment. We show that ZNF711 ablation prevents cardiomyocyte differentiation in the absence of retinoic acid, causing progenitors to be diverted more prominently to epicardial and other lineages. Retinoic acid rescues this shift in lineage commitment and promotes atrial cardiomyocyte differentiation, showing an interplay between ZNF711 and retinoic in cardiac lineage commitment. HIGHLIGHTS ![Figure][1] ### Competing Interest Statement R.P. is a cofounder of Pluriomics (Ncardia) and River BioMedics BV. The other authors declare no competing interests. [1]: pending:yes