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

TL;DR

A new tRNA fragment called CHAtRF contributes to heart enlargement by altering how a gene called Psmg4 is processed, offering potential new treatments and biomarkers for heart disease.

Contribution

Identifies CHAtRF as a novel tRF involved in cardiac hypertrophy through SRSF5-dependent regulation of Psmg4 splicing.

Findings

CHAtRF levels are elevated in cardiac hypertrophy in mice and humans.

CHAtRF interacts with SRSF5 to regulate Psmg4 pre-mRNA splicing, promoting exon 2 skipping.

CHAtRF deficiency reduces hypertrophy and improves heart function, while overexpression worsens it.

Abstract

tRNA-derived small RNAs (tsRNAs) or tRNA-derived fragments (tRFs) are an important class of regulatory molecules whose role in cardiac hypertrophy remains largely unknown. Here, we identified a novel tRF contributing to the regulation of cardiac hypertrophy that we termed CHAtRF (cardiac hypertrophy-associated tRF). The CHAtRF level was increased in mice and in patients with cardiac hypertrophy. CHAtRF deficiency attenuated angiotensin II (AngII)-induced cardiac hypertrophy and restored the heart function, while CHAtRF overexpression enhanced hypertrophic responses. Mechanistically, CHAtRF directly interacts with SRSF5 and blocks SRSF5 to bind with Psmg4 pre-mRNA, which mediates alternative splicing of Psmg4 pre-mRNA and promotes exon 2 skipping of Psmg4. CHAtRF-dependent alternative splicing of Psmg4 inhibits the expression of Psmg4 full-length isoform, resulting in progression of pathological hypertrophy. The ability of CHAtRF to regulate hypertrophy was confirmed in hiPSC-CMs, and CHAtRF serum levels are higher in individuals with myocardial hypertrophy or heart failure. Our findings reveal new insights into the previously unrecognized role of tsRNAs during cardiac hypertrophy, which provide potential novel therapeutic targets for pathological hypertrophy and might serve as potential biomarkers for diagnosing cardiac hypertrophy and heart failure.

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