38 research outputs found
RBM20 phosphorylation and its role in nucleocytoplasmic transport and cardiac pathogenesis
Arginine-serine (RS) domain(s) in splicing factors are critical for protein-protein interaction in pre-mRNA splicing. Phosphorylation of RS domain is important for splicing control and nucleocytoplasmic transport in the cell. RNA-binding motif 20 (RBM20) is a splicing factor primarily expressed in the heart. A previous study using phospho-antibody against RS domain showed that RS domain can be phosphorylated. However, its actual phosphorylation sites and function have not been characterized. Using middle-down mass spectrometry, we identified 16 phosphorylation sites, two of which (S638 and S640 in rats, or S637 and S639 in mice) were located in the RSRSP stretch in the RS domain. Mutations on S638 and S640 regulated splicing, promoted nucleocytoplasmic transport and protein-RNA condensates. Phosphomimetic mutations on S638 and S640 indicated that phosphorylation was not the major cause for RBM20 nucleocytoplasmic transport and condensation in vitro. We generated a S637A knock-in (KI) mouse model (Rbm(20S637A)) and observed the reduced RBM20 phosphorylation. The KI mice exhibited aberrant gene splicing, protein condensates, and a dilated cardiomyopathy (DCM)-like phenotype. Transcriptomic profiling demonstrated that KI mice had altered expression and splicing of genes involving cardiac dysfunction, protein localization, and condensation. Our in vitro data showed that phosphorylation was not a direct cause for nucleocytoplasmic transport and protein condensation. Subsequently, the in vivo results reveal that RBM20 mutations led to cardiac pathogenesis. However, the role of phosphorylation in vivo needs further investigation
Chiral effective field theories of the strong interactions
Effective field theories of the strong interactions based on the approximate
chiral symmetry of QCD provide a model-independent approach to low-energy
hadron physics. We give a brief introduction to mesonic and baryonic chiral
perturbation theory and discuss a number of applications. We also consider the
effective field theory including vector and axial-vector mesons.Comment: 22 pages, 9 figures, proceedings of "Many-Body Structure of Strongly
Interacting Systems", Mainz, Germany, Feb. 23-25 201
Co-occurring morphologically distinct algae support a diverse associated fauna in the intertidal zone of Araçá Bay, Brazil
Long-term self-renewing human epicardial cells generated from pluripotent stem cells under defined xeno-free conditions
Therapeutic cell differentiatio
Understanding How Message Receivers’ Communication Goals are Applied in Online Persuasion
Biochemical changes during embryogenesis of the Pacific halibut, Hippoglossus stenolepis (Schmidt)
RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing
Alternative splicing has a major role in cardiac adaptive responses, as exemplified by the isoform switch of the sarcomeric protein titin, which adjusts ventricular filling. By positional cloning using a previously characterized rat strain with altered titin mRNA splicing, we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression. The phenotype of Rbm20-deficient rats resembled the pathology seen in individuals with dilated cardiomyopathy caused by RBM20 mutations. Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20-dependent regulation of alternative splicing. In addition to titin (TTN), we identified a set of 30 genes with conserved splicing regulation between humans and rats. This network is enriched for genes that have previously been linked to cardiomyopathy, ion homeostasis and sarcomere biology. Our studies emphasize the key role of post-transcriptional regulation in cardiac function and provide mechanistic insights into the pathogenesis of human heart failure