P52Regulation of alternative splicing in the infarcted heart

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Our knowledge of gene expression patterns in heart disease has increased considerably in the last few years. Unfortunately, this information is largely incomplete, as it relates to whole gene expression and does not take into account the variety of isoforms that are generated for each gene by alternative splicing. Alternative splicing (AS) affects 94% of multi-exonic genes and is carefully controlled by a collection of cis-regulatory motifs and trans-regulatory proteins that are not completely understood. In the heart, AS plays a main role during embryonic development. However its role in adult heart pathophysiology is only now beginning to be unveiled. In this work we aimed to gain deeper understanding of the AS events taking place in the infarcted heart and how these are regulated.

Methods and Results

Using unbiased microarray analysis we found that genes related to AS, in particular trans-regulatory factors like hnRNPs or SR proteins, are downregulated in the remote myocardium of infarcted hearts, both in mice and humans. To gain insight into the global regulation of AS in heart failure, we analysed exon expression in myocardial samples from uninjured and infarcted hearts 7 and 28 days after infarction using exon microarrays. We found that less than 20% of the genes alternatively spliced were also differentially expressed between infarcted and uninjured hearts. Gene ontology analysis showed association of alternatively spliced genes with ion transport, intracellular signalling and cell adhesion. In contrast, differentially expressed genes fell into extracellular matrix, cell adhesion and metabolism categories, suggesting that the cellular processes regulated by AS are largely different from those controlled by changes in gene expression. Interestingly, investigation of AS changes in a mouse model of cardiac pressure overload showed that similar biological processes were affected in the hypertrophic and the infarcted hearts, although only partial overlap was observed between the lists of alternatively spliced genes in both models. Using decision trees, we identified the major regulatory and structural elements controlling the AS changes observed in the infarcted heart. While several regulatory motifs seemed to be important to distinguish between cryptic and skipped exons, exon length was one of the main elements accounting for the presence of alternative splicing in a gene.


Our results suggest there is a specific pattern of As changes associated with heart failure and that AS affects biological processes that are different from those controlled by changes in gene expression.

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