Marco Osterwalder, University of Bern, Switzerland

Marco Osterwalder, PhD
SNSF Assistant Professor
Department for BioMedical Research (DBMR)
University of Bern

Congenital heart disease (CHD) is the most common birth defect in humans and while the majority of associated variants map to non-coding genomic regions, the functional cis-regulatory architecture underlying development of the four-chambered mammalian heart remains insufficiently characterized. The GATA4 and HAND2 transcription factors (TFs) are CHD-associated key regulators of cardiac morphogenesis, and their inactivation leads to severe cardiac abnormalities, including ventricular, outflow tract and valve defects. Here, we used a combination of genome editing, single cell multiome profiling, region capture Hi-C and site-directed enhancer-reporter transgenesis in mouse embryonic hearts to functionally characterize the Hand2 and Gata4 enhancer landscapes at the cell type level. Genomic deletion of previously identified heart enhancers in Gata4 and Hand2 loci revealed a significant degree of transcriptional resilience, suggesting that redundant enhancer contributions are common in cardiac TF regulation. Concordantly, a subset of these enhancers was required for embryonic viability and entailed cardiac defects in a dosage sensitized background. To facilitate prediction of novel heart enhancers across cardiac cell types, we performed single-cell Multiome profiling during cardiac chamber expansion, which enabled genome-wide correlation of enhancer signatures with target gene activity, including the discovery of cell state transitions. In combination with chromatin capture, our single-cell resource allowed accurate identification of a novel set of far-upstream Hand2 heart enhancers located in a chromatin domain with cardiac-specific topology and cumulatively required for endocardial Hand2 expression, ventricular trabeculation and patterning of endocardial cushions. Our results reveal the cell type signatures of cardiac cis-regulatory elements during development and demonstrate critical functional contributions of conserved TF heart enhancers, important for cardiac morphogenesis and interpretation of CHD-associated genomic variants.

Biography

PhD in Cell Biology (2012) and Postdoctoral Researcher (2012-2014) at the Department for Biomedicine of the University of Basel, Switzerland. Postdoctoral Fellow (2014-2018) and Project Scientist (2018-2019) in the Mammalian Functional Genomics Group at Lawrence Berkeley National Laboratory (LBNL), Berkeley, California, USA. Awarded with the SNSF Eccellenza Professorial Fellowship in 2019. Since May 2020, Group Leader and Assistant Professor at the Department for BioMedical Research (DBMR) at the University of Bern, Switzerland.

The research in my group at the DBMR explores the cis-regulatory architecture and transcriptional enhancer landscapes in control of cardiac genes with essential functions in mammalian heart development, with the aim to define novel non-coding regions underlying congenital heart defects. Hereby, we are using a combination of functional genomics methods in mouse embryos such as CRISPR genome engineering, chromatin conformation capture and single-cell sequencing methods. In addition, we recently established hiPSC-derived cardiac organoids (cardioids) to study cardiac enhancer function in a human model of cardiogenesis.