Mirana Ramialison, Romaric Bouveret, Tram Doan, Danielle de Jong, Nicole Schonrock, Richard P Harvey
The Victor Chang Cardiac Research Institute, Sydney, Australia
ABSTRACT
The heart is a complex organ which successful development relies in part on complex feedback loops and cross-regulation between cardiac genes. Any alteration in these combinatorial interactions can be detrimental to the embryo and lead to congenital heart disease. Understanding which, how and when cardiac developmental genes interact with one another is key to comprehend disease mechanisms. Therefore, to gain insight into the complex interplay of genes governing heart development, we investigated the targets of cardiac transcription factors Nkx2-5, Gata4 and Tbx5 using DNA methyltransferase identification (DamID) in mouse cardiomyocytes at a genome-wide level. Using bioinformatics methods, we reconstructed the cardiac gene regulatory network centered on these key players. By applyingde novo motif discovery to the components of this network,we provide evidence that Elk transcription factors are novel players in cardiac development. We demonstrate that these proteins physically interact with cardiac core transcription factors in vitro. Finally, by using zebrafish as a model system, we provide in vivo functional evidence that Elk factors are essential for proper heart formation. Our systems levels approach led us to identify novel genes implicated in heart development and potentially responsible for heart malformations. Read More …
