Haploinsufficiency of brd4 causes adult-onset cardiac arrhythmia and cardiomyopathy in zebrafish

Bromodomain‑containing protein 4 (BRD4), a BET‑family epigenetic reader recognizing acetylated chromatin, is well‑studied in cancer and early cardiogenesis, yet its in vivo role in adult cardiac homeostasis remains unclear. Using CRISPR‑edited zebrafish ( Danio rerio ), we found brd4 homozygotes are embryonically lethal, whereas heterozygotes survive to adulthood and develop arrhythmogenic cardiomyopathy like defects: sinus‑arrest propensity, bradycardia, stress‑triggered sudden death, contractile impairment, sarcomere disarray, mitochondrial and desmosomal damage. Transcriptomics detected repressed focal‑adhesion and arrhythmia‑related genes; chromatin immunoprecipitation-quantitative PCR demonstrated Brd4 occupies their promoters. Targeted sequencing of BRD4 in 237 patients with sick sinus syndrome identified 5 rare missense variants, suggesting potential clinical relevance. Together, these findings identify brd4 haploinsufficiency as a cause of adult-onset cardiac arrhythmia and cardiomyopathy in vivo and suggest Brd4 as a dosage-sensitive epigenetic regulator of adult cardiac structural and electrical homeostasis.