BEX1 is an RNA-dependent mediator of cardiomyopathy [RIP-Seq]

Regulation of mRNA splicing, processing and stability is increasingly recognized as a critical control point in dynamically altering gene expression during stress or disease states. Very little is understood of this process in the heart despite the wide ranging changes in gene expression that occurs during heart failure; a disease of epidemic proportions in the western world. Here we identified BEX1 as a heart-failure-induced gene and identified its function as an mRNA binding protein responsible for enhancing expression of a subset of cardiac disease promoting genes. Modeling this increase in BEX1 that occurs in disease, BEX1 cardiac-specific overexpressing transgenic mice were generated and shown to have worse cardiac disease with stress stimulation while Bex1 gene-deleted mice were protected from insults that would otherwise promote heart failure. Since BEX1 was of unknown molecular function we performed a series of proteomic and interactive screening assays, which identified Bex1 as part of a large ribonucleoprotein processing complex involved in regulating pro-inflammatory mRNA expression in the heart. Specifically, induction of BEX1 augmented the stability and expression of AU-rich element containing mRNAs typically found within pro-inflammatory genes. Thus, BEX1 functions as an mRNA modulatory effector that augments pathology promoting gene expression during heart failure. Analysis of neonatale neonatale rat cardiomyocytes overexpressing Bex1 or beta galactosidase