A Retinoic Acid:YAP1 signaling axis controls atrial lineage commitment

Vitamin A/Retinoic Acid (RA) signaling is essential for heart development. In cardiac progenitor cells (CPCs), RA signaling induces the expression of atrial lineage genes while repressing ventricular genes, thereby promoting the acquisition of an atrial cardiomyocyte cell fate. To achieve this, RA coordinates a complex regulatory network of downstream effectors that is not fully identified. To address this gap, we applied a functional genomics approach (scRNAseq, scATACseq and ChIP-seq) to untreated and RA-treated human embryonic stem cells (hESCs)-derived CPCs. Unbiased analysis revealed that the Hippo effectors YAP and TEAD4 are integrated with the atrial transcription factor enhancer network, and that YAP1 is necessary for activation of RA-enhancers in CPCs. Furthermore, scRNAseq analysis of control and conditionally YAP KO mouse E7.75 embryos (Sox2cre) revealed that the expression of atrial lineage genes such as NR2F2 is compromised by YAP deletion in the CPCs of the second heart field. Accordingly, we found that YAP is required for the formation of an atrial chamber but is dispensable for the formation of a ventricle, in hESC-derived patterned cardiac organoids. Overall, our findings revealed that YAP1 is a non-canonical effector of RA signaling essential for the acquisition of atrial lineages during cardiogenesis. Overall design: Single-cell RNA sequencing (scRNAseq) data were obtained from E7.75 mouse embryos, including cYAP KO (Sox2cre:Yapflox/flox) and control (Sox2cre:Yapflox/+).