Abstract
Alternative splicing (AS) plays a major role in the generation of transcript diversity. In the heart, roles have been described for some AS variants, but the global impact and regulation of AS patterns are poorly understood. Here, we studied the AS profiles in heart disease, their relationship with heart development, and the regulatory mechanisms controlling AS dynamics in the mouse heart. We found that AS profiles characterized the different groups and that AS and gene expression changes affected independent genes and biological functions. Moreover, AS changes, specifically in heart disease, were associated with potential protein–protein interaction changes. While developmental transitions were mainly driven by the upregulation of MBNL1, AS changes in disease were driven by a complex regulatory network, where PTBP1 played a central role. Indeed, PTBP1 over-expression was sufficient to induce cardiac hypertrophy and diastolic dysfunction, potentially by perturb ing AS patterns.
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