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

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Frédéric Laurent, Ausra Girdziusaite, Julie Gamart, Iros Barozzi, Marco Osterwalder, Jennifer A. Akiyama, Joy Lincoln, Javier Lopez-Rios, Axel Visel, Aimée Zuniga, Rolf Zeller
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.

Graphical abstract

Teaser

Laurent et al. combine ChIP-seq with transcriptome analysis to identify the HAND2 target gene network that controls the EMT and mesenchymal cell migration during cardiac cushion formation in the atrioventricular canal (AVC). The HAND2 transcriptional targets include Snai1, whose re-expression in Hand2-deficient AVC explants partially restores mesenchymal cell migration.


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