Modeling and decoding the mechanisms oN left ventricular non compaction cardiomyopathy

Human left ventricular non-compaction cardiomyopathy (LVNC-CM) is a common, yet understudied, heart disease. Many LVNC-CM mutations impact developmental genes, including LMNA, suggesting that these cardiomyopathies have a developmental origin. Here, state-of-the-art 3D left-ventricle organoids and genome engineering are combined to model LMNA mutations. The impact of patient mutations on the differentiation and function of the […]

Interplay between epigenetics and metabolism in cardiac laminopathies

Mutations in LMNA cause dilated cardiomyopathy characterized by severe cardiac dysfunction and fatal ventricular arrhythmias, referred to as cardiac laminopathy. We recently found that LMNA-chromatin interactions control the expression of key metabolic enzymes, thereby enabling cardiovascular cells to adjust their metabolic needs. Importantly, Lmna-deficiency resulted in alterations of chromatin accessibility coupled to major changes in […]

Function and modulation of genomic cardiomyopathy enhancers

This project investigates cardiomyocyte enhancer-dependent molecular circuits of heart disease, with a focus on enhancers bound by the key cardiac transcription factor GATA4. We will use CRISPR-mediated epigenetic perturbation to dissect the functional contribution of cardiomyocyte enhancers and to modulate pathophysiological processes in vitro and in vivo. Furthermore, will we decode the impact of sequence […]

Targeting autophagy in cardiac remodeling via FYCO1

Dysregulation of autophagy contributes to the pathogenesis of cardiac remodelling and heart failure. Yet, the precise mechanisms and the therapeutic potential of cardiomyocyte autophagy are largely unknown. We will thus investigate whether modulation of autophagic flux via FYCO1/miR-106b, a novel pathway discovered in our preliminary work, will ameliorate adverse remodelling and cardiomyopathy due to genetic, […]

The role of inherited and acquired lipid accumulation for metabo-epigenetic control of cardiac function

Inherited neutral lipid storage disease with cardiomyopathy (NLSD-CM) is caused by mutations in PNPLA2, encoding a lipid droplet (LD)-associated protein, and is characterized by massive lipid accumulation. Using mouse models of genetic and acquired NLSD-CM, we have demonstrated the involvement of histone deacetylases (HDACs) in the development of diastolic dysfunction. The aim of the project […]