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RNA-Binding Protein RBM20 Upregulation Enhances Dilated Cardiomyopathy by Alternative Splicing of Atp6v0a1

ABSTRACT: Dilated cardiomyopathy (DCM) is a common cause of heart failure and mutations in RNA-binding motif protein 20 (RBM20) are linked to hereditary DCM. However, the role of unmutated RBM20 in idiopathic DCM is still ambiguous. In this study, we found that RBM20 expression was upregulated by the transcription factor c-JUN in idiopathic DCM. Mice with cardiomyocyte-specific RBM20 overexpression (RBM20cKI) resulted in heart failure with ventricle dilation and lysosome accumulation. Using LysoTracker and a tandem fluorescence RFP-GFP-LC3 reporter system, we elucidated RBM20 blocks autophagic flux in DCM by alkalinizing lysosomal pH. RNA sequencing revealed RBM20 overexpression leads to vacuolar H+-ATPase proton translocation domain subunit a1 (Atp6v0a1) exon6 and exon7 exclusion, which was validated by sanger sequencing and serial amplification product electrophoresis. Transgenic expression of full-length Atp6v0a1 isotype attenuated cardiac dysfunction and restored lysosomal acidification in RBM20cKI mice. Our data suggest that RBM20 activity precisely regulates various cellular process in cardiomyocytes and any therapy targeting RBM20 requires extra cautious.

ORGANISM(S): Mus musculus

PROVIDER: GSE281344 | GEO | 2026/01/01

REPOSITORIES: GEO

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RBM20 orchestrates cardiac pre-mRNA

Project description:The RNA-binding protein RBM20 has been implicated in dilated cardiomyopathy (DCM), a major cause of chronic heart failure. To determine how RBM20 regulates alternative splicing, we combined transcriptome-wide CLIP-seq, RNA-seq, and quantitative proteomics in cell culture, rat, and human hearts. Our analyses revealed a distinct RBM20 RNA-recognition element in predominantly intronic binding sites and linked repression of exon splicing with RBM20-binding near 3prime- and 5prime-splice sites. Our proteomic data show RBM20 interaction with U1- and U2-snRNPs and suggests splicing repression through spliceosome stalling at complex A. Among direct RBM20 targets are several genes involved in DCM as well as new genes not previously associated with the disease process. In human failing hearts, we demonstrate that reduced expression levels of RBM20 affect alternative splicing of several direct targets, indicating that differences in RBM20 gene expression may affect cardiac function. These findings reveal a new mechanism to understand the pathogenesis of human heart failure. The provided data files for RNA-seq contain information for reads that map to human RBM20 only.

2014-11-11 | E-MTAB-2572 | biostudies-arrayexpress

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Precise genomic editing of a pathogenic RBM20 mutation rescues dilated cardiomyopathy

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I536T variant of RBM20 affects splicing of cardiac structural proteins that are causative for developing dilated cardiomyopathy

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2022-10-05 | GSE201018 | GEO

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2023-06-19 | PXD038790 | Pride

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