The alternative splicing landscape of infarcted mouse heart identifies isoform level therapeutic targets

Area of Science:

• Molecular Biology
• Genomics
• Cardiovascular Science

Background:

• Alternative splicing generates transcript diversity crucial for cellular function and disease development.
• Cardiovascular disease (CVD), including myocardial infarction (MI) and ischemic reperfusion (IR) injury, involves significant transcriptomic alterations in heart tissue.
• Understanding these changes is vital for developing new therapeutic strategies.

Purpose of the Study:

• To characterize the alternative splicing landscape in the mouse heart during MI and IR injury.
• To establish a robust analytical pipeline for transcript-resolved differential expression profiling using long-read sequencing.
• To identify novel isoforms and regulated splicing events associated with cardiac injury.

Main Methods:

• Utilized Oxford Nanopore (ONT) full-length transcriptomic sequencing on murine models of MI and IR.
• Developed and implemented a computational pipeline for isoform identification, quantification, and differential expression analysis.
• Performed transcript-resolved profiling to capture the full spectrum of alternative splicing events.

Main Results:

• Successfully expanded the known catalog of mouse cardiac isoforms.
• Identified a significant number of differentially regulated alternative splicing events and transcripts during MI and IR.
• Revealed altered pathways related to metabolic reshaping and immunological response in the injured heart.

Conclusions:

• The study provides a comprehensive landscape of alternative splicing in the mouse heart under pathological conditions (MI and IR).
• The developed pipeline enables high-resolution analysis of transcriptomic complexity, applicable to various biological systems.
• Findings offer insights into the molecular mechanisms underlying cardiac injury and potential targets for CVD treatment.