PTBP1 promotes cardiac hypertrophy and diastolic dysfunction by modulating alternative splicing

Abstract

<jats:p>Alternative splicing (AS) plays a major role in the generation of transcript diversity. In the heart, roles have been described for some AS variants and individual RNA binding proteins (RBPs); however, the global regulation of AS in cardiac pathophysiology and its interaction with gene expression (GE) is poorly understood. In this study we aimed to identify the AS profiles that characterize heart disease and their relationship with heart development, and to investigate the regulatory mechanisms controlling AS dynamics in the mouse heart. We studied the AS profiles in several developmental stages and diseases using a total of 144 RNA-seq samples. We found that AS and GE changes affect genes involved in distinct biological functions and have different impact on protein-protein interaction networks. In contrast to cancer, most changes in AS in the heart tended to maintain protein interaction patterns. AS changes showed a stronger functional impact in heart development compared to adult cardiac diseases, and were mainly regulated by MBNL1. Regulatory patterns in cardiac disease were more complex, characterized by more interactions between regulatory proteins. We found PTBP1 as potential mediator of the partial re-expression of neonatal AS patterns in cardiac diseases. PTBP1 over-expression was sufficient to induce cardiac hypertrophy and diastolic dysfunction in adult mice.</jats:p>