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

• Published in: Nature communications Vol. 5; no. 1; p. 4907
• Main Authors: He, Aibin, Gu, Fei, Hu, Yong, Ma, Qing, Yi Ye, Lillian, Akiyama, Jennifer A., Visel, Axel, Pennacchio, Len A., Pu, William T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.09.2014; Nature Publishing Group
• Subjects: 38; 42; 631/337; 631/443/592/2726; 64/60; 692/699/75; Animals; Blotting, Western; Cardiomegaly - metabolism; Chromatin - metabolism; Chromatin Immunoprecipitation; Enhancer Elements, Genetic - genetics; GATA4 Transcription Factor - metabolism; Gene Expression Regulation, Developmental - physiology; Heart - embryology; High-Throughput Nucleotide Sequencing; Histones - metabolism; Humanities and Social Sciences; Luciferases; Mice; Mice, Transgenic; Morphogenesis - physiology; multidisciplinary; Real-Time Polymerase Chain Reaction; Science; Science (multidisciplinary); Statistics, Nonparametric
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms5907

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. Transcription factors (TFs) drive spatiotemporal patterns of gene expression that control organ development and disease responses. Here, He et al. show that chromatin occupancy of GATA4 varies between fetal, adult and hypertrophic heart to direct developmental stage- and disease-specific transcriptional programs.