RNA Isoform Atlas Enhances Understanding of Cardiovascular Disease

Recent advancements by Northwestern Medicine scientists have led to the creation of an extensive atlas detailing genetic coding sequences in both healthy adult hearts and those affected by heart failure. This comprehensive resource significantly advances the understanding of cardiac health by mapping RNA isoforms at the cellular level, providing critical insights into how gene splicing variations contribute to heart disease. The study, published in the journal Circulation, utilizes cutting-edge long-read single-nucleus RNA sequencing technology to profile thousands of full-length transcripts across different heart cell types, both in normal and diseased states.

The researchers applied this innovative approach to tissue samples from the left ventricles of healthy hearts and those with heart failure. By employing sophisticated computational analyses, they dissected the diversity of isoforms — different versions of RNA transcripts arising from the same gene — revealing widespread heterogeneity across cell types and states. For instance, in healthy hearts, around 30% of cell type-specific expressed genes produce multiple isoforms, maintaining essential cellular functions. Notably, over 300 genes consistently expressed in the heart, such as TNNI3 and ACTG1, display differential isoform patterns that are linked to specific cell functions.

In hearts affected by failure, the study uncovered 379 genes, including key ones like FRY, exhibiting significant shifts in isoform usage. These shifts often go unnoticed by traditional gene expression analyses but are crucial in understanding disease mechanisms. Lead author Timothy Pan emphasized the importance of these findings, stating that most genes involved in isoform changes are overlooked by standard methods, underscoring the value of their long-read sequencing approach.

This research not only sheds light on how alternative splicing impacts cardiac development and disease but also opens new avenues for developing targeted therapies. Gao, senior author of the study, highlighted that detailed full-length transcript data enable more precise identification of potential therapeutic targets and improve diagnostic accuracy. Previously, Gao and her team had developed a high-throughput method to profile full-length transcripts in cardiac cells, which was instrumental in generating this atlas.

The study's findings underscore the critical role of RNA isoforms in supporting normal cardiac functions and their involvement in cardiac diseases such as cardiomyopathy, arrhythmias, and heart failure. By leveraging this detailed isoform landscape, researchers can better understand disease progression and identify innovative treatment strategies.

More details of this groundbreaking research, led by Timothy Pan, can be found in the publication accessible through this link. This work marks a significant step forward in transcriptomics and cardiovascular medicine, offering hope for more effective interventions in the future.