RNA splicing in the heart Changing parts and performance

Proper RNA splicing is increasingly recognized as an important contributor to normal cardiac function, and abnormal splicing emerges as a major factor in (cardiac) disease. We focused on alternative splicing, a process in which different exons of a single gene can be in- or excluded in different ways in the mature mRNA transcript, giving rise to a much greater transcriptomic and proteomic diversity. How (differential) alternative splicing affects the heart is the main focus of this thesis. We summarize the current knowledge on RNA splicing, with a particular focus on the heart, and discuss the major and the less well-known minor spliceosome, factors controlling and regulating RNA splicing, the role of (alternative) splicing in cardiac development and disease, and the therapeutic potential of altering alternative splicing in the heart. In addition, we dissect the role of the RNA-binding proteins Rbm20, Rbm24, and Rbm38 in the heart, and look into how hypoxia influences alternative splicing in the heart. Lastly, we look into the biogenesis of (cardiac) circular RNAs, and couple this to the process of alternative splicing.