RBPMS regulates cardiomyocyte contraction and cardiac function through RNA alternative splicing

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• RNA Biology

Background:

• RNA binding proteins (RBPs) are critical for post-transcriptional gene regulation in the heart.
• RBPMS is essential for cardiac development via mRNA splicing.
• The role of RBPMS in the adult heart remains largely uncharacterized.

Purpose of the Study:

• To investigate the function of RBPMS in post-natal cardiac physiology.
• To elucidate the molecular mechanisms by which RBPMS regulates cardiac function.

Main Methods:

• Generation of a cardiac-specific RBPMS knockout mouse model.
• Proximity-dependent biotin identification and mass spectrometry to identify RBPMS interactors.
• RNA sequencing and RT-PCR to analyze gene expression and splicing.
• Minigene splicing reporter assays to determine splicing regulation.
• Human induced pluripotent stem cell-derived cardiomyocyte assays.

Main Results:

• Cardiac-specific RBPMS loss leads to severe cardiomyocyte contractile dysfunction, dilated cardiomyopathy, and premature lethality.
• RBPMS interacts with spliceosome components and other key cardiac RBPs like RBM20.
• RBPMS controls alternative splicing of sarcomeric genes (e.g., Ttn, Pdlim5, Nexn), producing novel protein isoforms.
• RBPMS recognizes tandem intronic CAC motifs for target gene splicing regulation.
• RBPMS knockdown impairs human cardiomyocyte contraction.

Conclusions:

• RBPMS is a critical regulator of cardiomyocyte contraction and overall cardiac function in adult mice.
• The mechanism involves RBPMS-mediated alternative splicing of sarcomeric genes.
• RBPMS plays a significant role in maintaining cardiac homeostasis post-natally.