The role of the AP-1 transcriptional complex during cardiac remodeling
Cardiovascular disease accounts for a large proportion of morbidity and mortality worldwide. We, and others, have shown that AP-1 transcription factors (TFs) play a role in remodeling the cardiomyocyte chromatin landscape in response to injury. Here, we aim to gain detailed insight into the molecular networks regulated by the AP-1 family of TFs during myocardial […]
The role of unconventional RNA-Binding proteins in the failing heart
In addition to the established role of RNA-binding proteins (RBPs) affecting post-transcriptional steps in gene expression, RNA-binding also regulate the function, activity, structure, or location of so called “unconventional” RBPs. This phenomenon has been termed “riboregulation”. We identified cardiomyocyte specific proteins surprisingly as RBPs, such as the sarcoplasmic reticulum calcium ATPase 2 (SERCA2a) and the […]
Impact of the translation elongation factor 1a on cardiac growth and function
Heart growth after birth or during disease involves increased protein synthesis and reduced protein degradation. The cardiac function of one putative regulator of both processes, the eukaryotic elongation factor 1 (EEF1A) was so far not studied, but recently a gene-mutation in this protein was associated with human cardiomyopathy. We therefore hypothesize that EEF1A, expressed in […]
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 […]