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

Cell Rep. 2017 May 23;19(8):1602-1613. doi: 10.1016/j.celrep.2017.05.004.


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.

Keywords: AVC; ChIP-seq; EMT; EndMT; RNA-seq; Snai1; cardiac cushion; endothelial to mesenchymal transition; mouse genetics; transcriptome.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Movement / genetics
  • Chromatin / metabolism
  • Endocardial Cushions / embryology*
  • Endocardial Cushions / metabolism*
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks*
  • Genome
  • Heart Valves / embryology*
  • Heart Valves / metabolism*
  • Mesoderm / cytology
  • Mesoderm / metabolism
  • Mice
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism
  • Transcription, Genetic


  • Basic Helix-Loop-Helix Transcription Factors
  • Chromatin
  • Hand2 protein, mouse
  • Snai1 protein, mouse
  • Snail Family Transcription Factors