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.
The Osterwalder Lab applies a combination of molecular genetics and functional genomics to explore the gene regulatory mechanisms that orchestrate mammalian heart formation. In our genomes, DNA-encoded “transcriptional enhancers” serve as key regulatory elements that can switch genes on and off in a cell type-specific manner and at great genomic distances (up to a million base pairs). 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 aims to functionally dissect the enhancer landscapes of critical cardiac transcription factor (TF) genes with the goal to understand how cardiac cell lineages emerge and how cardiac morphogenesis is wired in mammalian genomes. We are also in the process of establishing novel human iPSC-derived cardiac organoids to enable the study of human cardiogenesis in vitro and at high throughput. We aim to leverage our advanced mechanistic understanding of cardiac gene regulation not only to interpret human heart disease-associated genetic variants (diagnosis), but also to explore epigenome editing strategies for regenerative heart repair (therapeutic approaches).
The Osterwalder Lab started to operate at the Department for BioMedical Research (DBMR) in 2020 and is primarily supported by an SNSF Eccellenza fellowship, an SNSF NRP79 grant (to advance the 3Rs) and the Cardiology Department of the Bern University Hospital (Inselspital).
Left: Localized venous pole-restricted expression of the Shox2 transcription factor (green) essential for cardiac pacemaker function in the mouse embryonic heart myocardium (red).
Right: Cardiac enhancer activities (blue) validated in transgenic LacZ reporter assays (see Vista Enhancer Browser) following genome-wide identification based on transcription factor binding and histone modifications (Laurent et al., 2017).
from left to right:
Yasmine Lydia Tschuy (Master Student BMS), Vincent Rapp (PhD Student), Matteo Zoia (PhD Student), Virginie Tissières (Lab Manager & Research Technician), Christian Zuppinger (Collaborator NRP79 HeartX), Virginia Roland (PhD Student), Marco Osterwalder (Group Leader), Ekapaksi Wisnumurti (Master Student MLS)