A5037102400- RNA Research and Splicing
- Cardiomyopathy and Myosin Studies
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Viral Infections and Immunology Research
- Cardiac Fibrosis and Remodeling
- MicroRNA in disease regulation
- Cancer-related molecular mechanisms research
- Signaling Pathways in Disease
- Circular RNAs in diseases
- Cardiovascular Effects of Exercise
- CRISPR and Genetic Engineering
- Cell Adhesion Molecules Research
- Cardiac, Anesthesia and Surgical Outcomes
- Peroxisome Proliferator-Activated Receptors
- Nuclear Structure and Function
- Cancer, Hypoxia, and Metabolism
- Genetic Neurodegenerative Diseases
- Protein Kinase Regulation and GTPase Signaling
- Genomics and Chromatin Dynamics
- Health and Medical Research Impacts
- Health Systems, Economic Evaluations, Quality of Life
- Cardiac electrophysiology and arrhythmias
- Mechanical stress and fatigue analysis
- Nuclear Receptors and Signaling
German Centre for Cardiovascular Research
2020-2023
Heidelberg University
2018-2022
University Hospital Heidelberg
2018-2022
Amsterdam University Medical Centers
2020
Amsterdam UMC Location University of Amsterdam
2013-2018
University of Amsterdam
2014-2016
Aarhus University Hospital
2016
Amsterdam UMC Location Vrije Universiteit Amsterdam
2016
Cincinnati Children's Hospital Medical Center
2010
Medical College of Wisconsin
2010
RNA-binding motif protein 20 (RBM20) is essential for normal splicing of many cardiac genes, and loss RBM20 causes dilated cardiomyopathy. Given its role in splicing, we hypothesized an important forming circular RNAs (circRNAs), a novel class noncoding RNA molecules.To establish the formation circRNAs heart.Here, performed circRNA profiling on ribosomal depleted from human hearts identified expression thousands circRNAs, with some them regulated disease. Interestingly, 80 to be expressed...
Background: Mutations in RBM20 (RNA-binding motif protein 20) cause a clinically aggressive form of dilated cardiomyopathy, with an increased risk malignant ventricular arrhythmias. is splicing factor that targets multiple pivotal cardiac genes, such as Titin (TTN) and CAMK2D (calcium/calmodulin-dependent kinase II delta). Aberrant TTN thought to be the main determinant RBM20-induced but not likely explain Here, we investigated extent which mutation carriers have arrhythmias explore...
The overloaded heart remodels by cardiomyocyte hypertrophy and interstitial fibrosis, which contributes to the development of failure. Signalling via TGFβ-pathway is crucial for this remodelling. Here we tested hypothesis that microRNAs in regulate remodelling process inhibition TGFβ-pathway. We show miRNA-15 family, found be up-regulated multiple species, inhibits targeting TGFBR1 several other genes within pathway directly or indirectly, including p38, SMAD3, SMAD7, endoglin. Inhibition...
Mutations in the RS-domain of RNA-binding motif protein 20 (RBM20) have recently been identified to segregate with aggressive forms familial dilated cardiomyopathy (DCM). Loss RBM20 rats results missplicing sarcomeric gene titin ( TTN ). The functional and physiological consequences mutations outside mutational hotspot not explored date. In this study, we investigated pathomechanism DCM caused by a novel mutation human cardiomyocytes. We family carrying (RBM20 E913K/+ ) glutamate-rich region...
The transcriptional code that programs maladaptive cardiac hypertrophy involves the zinc finger-containing DNA binding factor GATA-4. highly related transcription GATA-6 is also expressed in adult heart, although its role controlling hypertrophic program unknown.To determine of and homeostasis.Here, we performed a cardiomyocyte-specific conditional gene targeting approach for Gata6, as well transgenic to overexpress mouse heart. Deletion Gata6-loxP with Nkx2.5-cre produced late embryonic...
A-type lamins are a major component of the nuclear lamina. Mutations in LMNA gene, which encodes A and C, cause set phenotypically diverse diseases collectively called laminopathies. While adult null mice show various symptoms typically associated with laminopathies, effect loss lamin A/C on early post-natal development is poorly understood. Here we developed novel mouse (LMNAGT-/-) based genetrap technology analyzed its development. We detect transcripts heart, outflow tract, dorsal aorta,...
Circular RNAs (circRNAs) are a relatively new class of RNA molecules, and knowledge about their biogenesis function is still in its infancy. It was recently shown that alternative splicing underlies the formation circular (circRNA) arising from Titin (TTN) gene. Since main mechanism by which circRNAs formed unclear, we hypothesized splicing, particular exon skipping, major driver circRNA production. We performed sequencing on human mouse hearts, mapped events, overlaid these with expressed...
Dilated cardiomyopathy is the second most common cause for heart failure with no cure except a high-risk transplantation. Approximately 30% of patients harbor heritable mutations which are amenable to CRISPR-based gene therapy. However, challenges related delivery editing complex and off-target concerns hamper broad applicability CRISPR agents in heart. We employ combination viral vector AAVMYO superior targeting specificity muscle tissue base editors repair patient cardiac splice factor...
Distinct stressors may induce heart failure. As compensation, β-adrenergic stimulation enhances myocardial contractility by elevating cardiomyocyte intracellular Ca(2+) ([Ca(2+)]i). However, chronic promotes adverse cardiac remodelling. Cardiac expression of nuclear receptor Nur77 is enhanced stimulation, but its role in remodelling still unclear. We show high and rapid upregulation cardiomyocytes stimulated with agonist isoproterenol. knockdown culture resulted hypertrophic cardiomyocytes....
Abstract The RNA-binding protein Rbm24 has recently been identified as a pivotal splicing factor in the developing heart. Loss of mice disrupts cardiac development by governing large number muscle-specific events. Since knockout are embryonically lethal, role adult heart remained unexplored. Here, we used adeno-associated viruses (AAV9) to investigate effect increased levels mouse Using high-resolution microarrays, found 893 differentially expressed genes and 1102 differential events 714...
The importance of tightly controlled alternative pre-mRNA splicing in the heart is emerging. RNA binding protein Rbm24 has recently been identified as a pivotal cardiac splice factor, which governs sarcomerogenesis by controlling expression isoforms. Rbm38, homolog Rbm24, also implicated processes such splicing, stability and translation, but its function currently unknown. Here, we investigated role Rbm38 healthy diseased adult mouse heart. In contrast to heart- skeletal muscle-enriched...
RBM20 cardiomyopathy is an arrhythmogenic form of dilated caused by mutations in the splicing factor RBM20. A recent study found a more severe phenotype male patients with than female patients. Here, we aim to determine sex differences animal model and investigate potential underlying mechanisms. In addition, gender clinical parameters novel patient cohort. We characterized Rbm20 knockout (KO) mouse model, show that key targets, cardiac function, arrhythmia susceptibility do not differ...
The pathology of heart failure is characterized by poorly contracting and dilated ventricles. At the cellular level, this associated with lengthening individual cardiomyocytes loss sarcomeres. While it known that transcription factor myocyte enhancer factor-2 (MEF2) involved in cardiomyocyte remodelling, underlying mechanism remains to be elucidated. Here, we aim mechanistically link MEF2 target genes sarcomeres during remodelling.Neonatal rat overexpressing elongated lost their sarcomeric...
Abstract Dilated cardiomyopathy (DCM) is the second most common cause for heart failure with no cure except a high-risk transplantation. Approximately 30% of DCM patients harbor heritable mutations which are amenable to CRISPR-based gene therapy 1 . However, challenges related delivery editing complex and off-target concerns hamper broad applicability CRISPR agents in 2 We employed combination viral transfer vector AAVMYO superior targeting specificity muscle tissue 3 base editors repair...
Abstract RNA-binding proteins are key regulators of post-transcriptional processes such as alternative splicing and mRNA stabilization. Rbm24 acts a regulator in heart skeletal muscle, is essential for sarcomere assembly. Homozygous inactivation mice disrupts cardiac development results embryonic lethality around E12.5. In the present study, we generated somatic knockout (KO) investigated effects reduced levels adult heart. Due to KO mice, examined structure function heterozygotes (HETs)....