Multi-Omics and Single-Cell Sequencing Drive Exploration of Alternative Splicing in Heart Disease

What is Alternative Splicing?

From the roughly 20,000 protein-coding genes in humans, it is predicted that more than 70,000 variations (isoforms) of proteins can be created. How is this possible? In the central dogma of molecular biology, DNA (a gene) gives rise to RNA (mRNA) which gives rise to a protein. A process called alternative splicing adds an extra step: the initial RNA, called pre-mRNA, can have different functional domains (exons) “spliced” together. That is to say, one pre-mRNA with three exons (A, B and C) has multiple possible fates: an mRNA containing exons ABC, AB, BC, and so on, resulting in proteins with different functions.

Alternative Splicing in Heart Disease

Given its central role in determining the ultimate functional output of a gene, alternative splicing is a tightly regulated process. As such, disruptions to that regulatory network can cause diseases. The function of alternative splicing in heart disease was highlighted in a recent review for Nature Reviews Cardiology, as it plays such a central role in both normal cardiac development and in healthy physiological adaptations of the heart like exercise-induced hypertrophy.

Alterations to both splice sites and splicing factors can contribute to cardiac pathophysiology: in fact, up to 10% of genetic mutations associated with heart disease reportedly affect splice sites. The resultant under- or mis-expression of key protein isoforms is what leads to these complex cardiomyopathies, affecting heart muscle contraction ability and cell signaling.

How Advances in Sequencing Technology Improve Splicing Analysis

Advances in long-read sequencing, single-cell sequencing approaches and multi-omics have allowed researchers to better characterize which isoforms are expressed at different stages of development or during heart failure, as well as facilitating the identification of splice sites or splicing factors that may be involved. Fortunately, these splice sites and splicing factors can serve as therapeutic targets once identified. Though less commonly implicated in disease, splicing factors can be targeted more “easily” using small molecule or antisense oligonucleotide approaches. The more commonly found splice site mutations are being tested with trans-splicing and gene editing approaches.

Genomic and transcriptomic-based approaches are useful both for diagnostics to inform the direction of treatment as well as for developing these experimental therapies to regulate splicing. Recognizing that splice site variants play a larger role in heart disease than previously known will drive future research, including advances in the bioinformatic techniques used to analyze splicing-related dysfunction.

Outsourcing Bioinformatics Analysis: How Bridge Informatics Can Help

Many of our clients at Bridge Informatics are pursuing these kinds of research questions with sophisticated bioinformatics approaches. From pipeline development and software engineering to deploying existing bioinformatics tools, Bridge Informatics can help you on every step of your research journey. As experts across data types from cutting-edge sequencing platforms, we can help you tackle the challenging computational tasks of storing, analyzing and interpreting genomic and transcriptomic data. Bridge Informatics’ bioinformaticians are trained bench biologists, so they understand the biological questions driving your computational analysis. Click here to schedule a free introductory call with a member of our team.

Jane Cook, Biochemist & Content Writer, Bridge Informatics

Jane Cook, leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email or

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