SETD2 as an epigenetic sentinel of transcriptional fidelity in cardiomyocytes: a mechanistic link to heart failure

Epigenetic modulations are pivotal in heart disease progression, yet the specific influence of epigenetic alterations on transcription initiation and elongation in heart failure (HF) is poorly understood. This study focuses on the SETD2-H3K36me3 axis, a key conserved regulator of transcriptional initiation fidelity. We found that SETD2 and H3K36me3 levels were significantly decreased in failing human and mouse hearts, coinciding with a profound increase in cryptic transcripts. Cardiac-specific Setd2 knockout (KO) caused progressive HF in the mice. By comprehensive multi-omics sequencing and functional assessments, we demonstrated that SETD2 deficiency led to substantial increases in unannotated intragenic transcription and translation initiation events, resulting in the emergence of aberrant transcripts and an accumulation of micropeptides, therefore, exacerbating cardiac function. Conversely, overexpressing SETD2 protected the heart from pressure overload-induced HF and attenuated cryptic transcript accumulation, suggesting that maintaining transcription integrity is crucial for heart health. Our findings reveal a novel association between transcription fidelity disruption and HF, offering potential new directions for therapeutic intervention.