HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development

Highlights

• HAND2 controls development of the AVC cardiac cushions forming mitral/tricuspid valves

• HAND2 is a key regulator of the EMT underlying cardiac cushion mesenchyme formation

• Identification of the HAND2 target gene networks that control EMT and AVC development

• HAND2 acts upstream of the EMT key regulator Snai1 in AVC and other embryonic tissues

Summary

The HAND2 transcriptional regulator controls cardiac development, and we uncover additional essential functions in the endothelial to mesenchymal transition (EMT) underlying cardiac cushion development in the atrioventricular canal (AVC). In Hand2-deficient mouse embryos, the EMT underlying AVC cardiac cushion formation is disrupted, and we combined ChIP-seq of embryonic hearts with transcriptome analysis of wild-type and mutants AVCs to identify the functionally relevant HAND2 target genes. The HAND2 target gene regulatory network (GRN) includes most genes with known functions in EMT processes and AVC cardiac cushion formation. One of these is Snai1, an EMT master regulator whose expression is lost from Hand2-deficient AVCs. Re-expression of Snai1 in mutant AVC explants partially restores this EMT and mesenchymal cell migration. Furthermore, the HAND2-interacting enhancers in the Snai1 genomic landscape are active in embryonic hearts and other Snai1-expressing tissues. These results show that HAND2 directly regulates the molecular cascades initiating AVC cardiac valve development.