Congenital heart disease (CHD) represents the most common birth defect in humans and is affecting about 1% of all live-born infants. Despite major advances in biomedicine and surgery, CHDs remain a significant cause of morbidity and mortality in both children and adults. While congenital heart defects frequently result from perturbation of developmental gene networks, incomplete understanding of the underlying regulatory mechanisms often limits progress in the diagnosis, prevention and treatment of CHD.

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We apply a combination of molecular genetics and functional genomics to study the gene regulatory mechanisms that orchestrate formation of the four-chambered heart during embryogenesis and that can trigger CHD when defective. In mammalian genomes, DNA-encoded “transcriptional enhancers” serve as key regulatory modules that can switch genes on and off in a cell type-specific manner and at great linear genomic distances from their target gene(s) (up to >1M basepairs). Importantly, sequence mutation or perturbation in cardiac enhancers has been linked to cardiac malformation and CHD. However, despite the availability of genome-wide technologies, prediction of genomic enhancer function remains challenging, and the cis-regulatory landscapes of most cardiac genes are still underexplored. Our research has the goal to functionally annotate regulatory DNA in human genomes by dissecting the enhancer landscapes underlying the complex expression patterns of key cardiac genes, such as developmental transcription factors (TF). Such mechanistic understanding of cardiac gene regulation will not only help us to better understand how cardiac cell lineages emerge and how cardiac morphogenesis is wired in mammalian genomes, but will also be valuable for advanced interpretation of genomic heart disease-associated variants from patients and enable to explore genetic strategies for regenerative heart repair.

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