RBM20 orchestrates cardiac pre-mRNA

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 3 prime- and 5 prime-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 portion of the data set in ENA contains the CLIP-seq data only. See ArrayExpress E-MTAB-2572 for the RNA-seq data processed files.