Transcriptional control of cardiac conduction system development and function

The cardiac conduction system initiates and propagates the electrical impulse that is required for the coordinated contraction of the heart. Defects in its development or function can lead to conduction disorders, life-threatening arrhythmias and cardiac death. Insights into the mechanisms underlying the complex development of the various components of the heart is therefore crucial. In this thesis, we studied the transcriptional regulation of several genes involved in cardiac conduction. We summarized current knowledge regarding the transcriptional networks underlying cardiac development, with emphasis on the cardiac conduction system, and discussed how defects in these networks contribute to conduction disorders. Furthermore, we investigated the evolutionary conservation of Isl1, a transcription factor important for conduction system development and pacemaker function in mammals, and studied its role in the zebrafish heart. We also focused on the transcriptional regulation of Tbx3, encoding a transcription factor crucial for conduction system development and function, and Kcnh2, a target gene of Tbx3 encoding a potassium channel responsible for fast repolarization in chamber cardiomyocytes in the human heart. We defined the regulatory domains of both genes, characterized several regulatory DNA elements involved in their complex regulation both in vitro and in vivo, and assessed the effect of common trait-associated variation on their activity. Combined, the results in this thesis add to our understanding of the complex regulation of cardiac gene expression and reflects on how common trait-associated variation can contribute to disease.