GATA4 blocks squamous epithelial cell gene expression in human esophageal squamous cells

GATA4 promotes columnar epithelial cell fate during gastric development. When ectopically expressed in the developing mouse forestomach, the tissue emerges as columnar-like rather than stratified squamous with gene expression changes that parallel those observed in the pre-malignant squamous to columnar metaplasia known as Barrett's esophagus (BE). GATA4 mRNA up-regulation and gene amplification occur in BE and its associated cancer, esophageal adenocarcinoma (EAC), and GATA4 gene amplification correlates with poor patient outcomes. Here, we explored the effect of ectopic expression of GATA4 in mature human esophageal squamous epithelial cells. We found that GATA4 expression in esophageal squamous epithelial cells compromised squamous cell marker gene expression and up-regulated expression of the canonical columnar cell cytokeratin KRT8. We observed GATA4 occupancy in the p63, KRT5, and KRT15 promoters, suggesting that GATA4 directly represses expression of squamous epithelial cell marker genes. Finally, we verified GATA4 protein expression in BE and EAC and found that exposure of esophageal squamous epithelial cells to acid and bile, known BE risk factors, induced GATA4 mRNA expression. We conclude that GATA4 suppresses expression of genes marking the stratified squamous epithelial cell lineage and that this repressive action by GATA4 may have implications in BE and EAC.

Automated summary

The study showed the critical role of GATA4 in determining the fate of columnar epithelial cells during gastric and esophageal development. In diseases like Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), up-regulation of GATA4 expression is associated with poor patient outcomes, and its ectopic expression suppresses squamous cell marker gene expression. This suggests that GATA4 may play a repressive role in BE and EAC by inhibiting genes marking the stratified squamous epithelial cell lineage.