Dynamic GATA4 enhancers shape the chromatin landscape central to heart development and disease

Abstract

How stage-specific enhancer dynamics modulate gene expression patterns essential for organ development, homeostasis and disease is not well understood. Here, we addressed this question by mapping chromatin occupancy of GATA4 - a master cardiac transcription factor - in heart development and disease. We find that GATA4 binds and participates in establishing active chromatin regions by stimulating H3K27ac deposition, which facilitates GATA4-driven gene expression. GATA4 chromatin occupancy changes markedly between fetal and adult heart, with a limited binding sites overlap. Cardiac stress restored GATA4 occupancy to a subset of fetal sites, but many stress-associated GATA4 binding sites localized to loci not occupied by GATA4 during normal heart development. Collectively, our data show that dynamic, context-specific transcription factors occupancy underlies stage-specific events in development, homeostasis and disease.