Random monoallelic gene expression in inherited cardiomyopathies
About 2-5% of autosomal genes can be expressed in a clonally stable, random monoallelic manner in some cell types. Importantly, genes displaying random monoallelic expression (RME) are often associated with autosomal dominant disorders, including skeletal and cardiac myopathies. Despite the major implications of monoallelic expression for disease – particular in the context of heterozygous mutations […]
Dysregulation of mRNA decay in MYBPC3 hypertrophic cardiomyopathy
In hypertrophic cardiomyopathy (HCM), the underlying mutations frequently affect MBPC3 and cause premature termination of MBPC3 protein synthesis. We observed that nonsense-mediated mRNA decay (NMD) activation plays an important role in the pathogenesis of HCM. Here we propose to (I) investigate the effect of NMD activation on gene regulation in healthy and diseased human induced […]
STAR family function and interaction with RBM20 for intervening alternative splicing
Deregulation of alternative splicing of sarcomeric genes is a hallmark of heart failure. To better understand the cardiac splicing dynamics, we aimed to determine the in vivo function of Sam68-Like mammalian protein 2 (SLM2) splicing factor, that we have previously discovered to oppose cardiac RBM20 splicing. Here, we utilized a mouse model of inducible cardiomyocyte […]
Decoding the regulatory network of RBM20
A06 pursues a novel strategy to treat an inherited form of dilated cardiomyopathy caused by mutations in the gene RBM20. DCM patients usually harbor one defective copy of RBM20 while the other one is still intact (haploinsufficieny). Upregulation of the “healthy” allele presents a pathway to restore RBM20 activity. By systematically manipulating the expression of […]
Role of the splice target CAMK2D in RBM20 cardiomyopathy
Mutations in RBM20 cause a clinically aggressive form of dilated cardiomyopathy. RBM20 is a splicing factor that targets multiple cardiac genes, such as TTN and CAMK2D. Preliminary data shows that CAMK2D mediates cardiac dysfunction in RBM20 cardiomyopathy. Therefore, we ask how CAMK2D mediates RBM20 cardiomyopathy. We found that Camk2d-dependent LMNA phosphorylation is increased in the […]
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 […]