Dr. Leo Kurian is a Professor at Goethe University Frankfurt working with integrative RNA biology of cardiac development and disease.
Background
Pre-mRNA splicing is a fundamental step in gene expression, which allows programmed and precise reconstitution of the segmented organization of coding information in DNA. The decision-making process at each splice site is a complex, context-dependent computation influenced by proximal and distal sequence motifs, the splicing factors that interact with them, and their functional interactions with spliceosome complexes. This complexity is magnified in the heart, where cell type-specific splicing decisions are known to impact cardiac development and cardiac function. Its precise regulation is critical, as misregulation can lead to catastrophic cardiac outcomes.
Our study addresses the context-specific decision-making involved in splicing at the molecular level, focusing on a key cardiac splicing factor. Although ubiquitously expressed, loss of this splicing factor in the heart decouples cardiogenesis from sarcomere generation and cardiac function. We will present data demonstrating how a cardiac splicing factor stabilizes spliceosome complexes at weak 5' splice sites on mRNAs crucial to cardiac function, thereby ensuring splicing fidelity. Consequently, the loss of this factor results in the disruption of the cardiac splicing code and the nuclear retention of aberrantly spliced cardiac mRNAs, culminating in the development of a heart devoid of sarcomeres and incapable of beating.