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 gene regulatory mechanisms that orchestrate mammalian heart formation. In particular, our research is focusing on the identification and characterization of transcriptional heart enhancers, short gene regulatory switches often hidden in the vast non-protein coding portion of our genomic DNA. Enhancers represent the main class of cis-regulatory elements in mammalian genomes and are known to control transcription of essential genes during development and adulthood. Importantly, sequence mutation or perturbation in cardiac enhancers has the potential to trigger cardiac malformation and CHD. However, despite recent advances in genome-wide enhancer prediction, functional profiling of heart enhancers remains challenging and the cis-regulatory landscapes of most key cardiac genes remain underexplored. Our research has the aim to functionally dissect the enhancer landscapes of important cardiac regulator genes, such as cardiac transcription factors, in order to define novel cis-regulatory principles underlying heart formation and to identify cis-regulatory modules which can act as a substrate for pathological mutations and CHD.
We are also exploring novel strategies for CRISPR-mediated epigenome editing to study the dynamic enhancer landscapes involved in cardiac reprogramming, a genetic approach with therapeutic potential for in-situ cardiac repair.
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).
Supported by an SNSF Eccellenza grant, the Osterwalder Lab started to operate in 2020 at the Department for BioMedical Research (DBMR) of the University of Bern.