GATA-dependent regulatory switches establish atrioventricular canal specificity during heart development.
The embryonic vertebrate heart tube develops an atrioventricular canal that divides the atrial and ventricular chambers, forms atrioventricular conduction tissue and organizes valve development. Here we assess the transcriptional mechanism underlying this localized differentiation process. We show that atrioventricular canal-specific enhancers are GATA-binding site-dependent and act as switches that repress gene activity in the chambers. We find that atrioventricular canal-specific gene loci are enriched in H3K27ac, a marker of active enhancers, in atrioventricular canal tissue and depleted in H3K27ac in chamber tissue. In the atrioventricular canal, Gata4 activates the enhancers in synergy with Bmp2/Smad signalling, leading to H3K27 acetylation. In contrast, in chambers, Gata4 cooperates with pan-cardiac Hdac1 and Hdac2 and chamber-specific Hey1 and Hey2, leading to H3K27 deacetylation and repression. We conclude that atrioventricular canal-specific enhancers are platforms integrating cardiac transcription factors, broadly active histone modification enzymes and localized co-factors to drive atrioventricular canal-specific gene activity.
Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands.
Sonia
S
Stefanovic
Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands.
Phil
P
Barnett
Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands.
Karel
K
van Duijvenboden
Developmental Biochemistry, Biocenter and Comprehensive Heart Failure Center, University of Wuerzburg, Am Hubland, D-97074 Wuerzburg, Germany.
David
D
Weber
Developmental Biochemistry, Biocenter and Comprehensive Heart Failure Center, University of Wuerzburg, Am Hubland, D-97074 Wuerzburg, Germany.
Manfred
M
Gessler
Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands.
Vincent M
VM
Christoffels
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D050991:GATA4 Transcription Factor / Q000235:genetics*; D005697:Galactosides; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006321:Heart / Q000196:embryology*; D006351:Heart Valves / Q000196:embryology* / Q000378:metabolism; D007150:Immunohistochemistry; D007211:Indoles; D051379:Mice; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D050991:GATA4 Transcription Factor; D005697:Galactosides; C484171:Gata4 protein, mouse; D007211:Indoles; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside