Abstract P325: Novel Insights in Transcriptome Remodeling Associated with Heart Failure Revealed by Deep RNA Sequencing

Abstract

The complexity of transcriptome and proteome is contributed by alternative splicing of RNA. Altered RNA splicing is also implicated in many human diseases including cancer. However, little knowledge is available about the scope of alternative splicing at whole genome level in heart diseases and even less about the mechanisms underlying the regulation of mRNA splicing in response to pathological injury in heart. In order to investigate the key alternative splicing events associated with cardiac pathogenesis, we used high-throughput RNA-Seq to profile total transcriptome in mouse heart failure induced by pressure-overload. From preliminary data, we identified >1000 novel exons that have not been reported in any published database. Many of the novel exons are detected in genes with potential importance in cardiac gene regulation and signal transduction. In addition, we have also identified a significant number of differentially expressed exons between normal and diseased hearts, supporting the notion that differential RNA splicing is associated with the onset of heart failure. Interestingly, the differential splicing events observed in failing hearts were also detected in neonatal mouse hearts, suggesting that differential RNA splicing is a part of the “fetal” gene expression program in diseased hearts. Furthermore, we have also validated some of these changes in human heart failure samples, supporting the clinic relevance of these findings. In summary, this study suggests that development of heart failure is associated with alternative RNA splicing events at genome level. Further studies on the functional consequences of differential RNA splicing and the underlying regulatory mechanisms in heart will advance our understanding to this important disease.