A retinoic acid:YAP1 signaling axis controls atrial lineage commitment

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Cardiovascular Research

Background:

• Retinoic acid (RA) signaling is crucial for inducing atrial lineage gene expression and cell fate in cardiac progenitor cells (CPCs).
• The precise regulatory network downstream of RA signaling that governs this process is not fully understood.

Purpose of the Study:

• To identify novel downstream effectors of RA signaling in human embryonic stem cell (hESC)-derived CPCs.
• To elucidate the role of the Hippo pathway, specifically YAP1 and TEAD4, in RA-mediated atrial lineage specification.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) and single-nucleus ATAC sequencing (snATAC-seq) were employed on hESC-derived CPCs.
• Functional genomics approaches were used to analyze gene expression and chromatin accessibility.
• Yap1 deletion in mouse embryos and hESC-derived heart organoid models were utilized for in vivo and in vitro validation.

Main Results:

• Unbiased analysis identified YAP1 and TEAD4 as key Hippo pathway effectors integrated into the atrial transcription factor network.
• YAP1 was shown to activate RA-responsive enhancers in CPCs, promoting the expression of RA-induced genes like Nr2f2.
• Yap1 deletion in mouse embryos impaired RA-induced gene expression in second heart field CPCs, and YAP1 regulated atrial chamber formation in hESC-derived organoids.

Conclusions:

• YAP1 functions as a critical mediator of RA signaling in the induction of atrial lineages during cardiogenesis.
• YAP1 cooperates with RA signaling to establish atrial cell fate and regulate atrial chamber development, but is dispensable for ventricle formation.