CHAtRF Modulates Cardiac Hypertrophy via SRSF5-Dependent Regulation of Psmg4 Alternative Splicing

Area of Science:

• Molecular Biology
• Cardiovascular Research
• RNA Biology

Background:

• tRNA-derived small RNAs (tsRNAs/tRFs) are emerging regulatory molecules.
• The role of tsRNAs in cardiac hypertrophy is largely unexplored.

Purpose of the Study:

• To identify and characterize novel tsRNAs involved in cardiac hypertrophy.
• To elucidate the molecular mechanisms underlying tsRNA regulation in pathological cardiac remodeling.

Main Methods:

• Identification of a novel tRF, termed CHAtRF (cardiac hypertrophy-associated tRF).
• Assessment of CHAtRF levels in mouse models and human cardiac hypertrophy patients.
• Investigation of CHAtRF's functional role using deficiency and overexpression models.
• Mechanistic studies involving RNA-protein interactions and alternative splicing analysis.
• Validation in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).

Main Results:

• CHAtRF levels are significantly increased in cardiac hypertrophy.
• CHAtRF deficiency attenuates angiotensin II-induced cardiac hypertrophy and improves cardiac function.
• CHAtRF overexpression exacerbates hypertrophic responses.
• CHAtRF directly interacts with SRSF5, inhibiting Psmg4 pre-mRNA splicing and promoting exon 2 skipping.
• Reduced Psmg4 full-length isoform expression contributes to pathological hypertrophy.
• Elevated CHAtRF serum levels correlate with myocardial hypertrophy and heart failure.

Conclusions:

• CHAtRF plays a critical role in regulating cardiac hypertrophy.
• CHAtRF acts by modulating Psmg4 alternative splicing via SRSF5 interaction.
• CHAtRF represents a potential therapeutic target and diagnostic biomarker for cardiac hypertrophy and heart failure.