Histone Demethylase KDM5A Is Activated and Pathogenic in a Mouse Model of LMNA-Cardiomyopathy

Heart failure is associated with widespread epigenetic remodeling in cardiomyocytes, but the chromatin regulators driving this process remain poorly defined. We identify the histone H3K4 demethylase KDM5A as a key epigenetic mediator of heart failure in a cardiomyocyte-specific lamin A-deficient mouse model. Disease-associated activation of KDM5A leads to redistribution of promoter histone H3 lysine 4 trimethylation and repression of genes regulating sarcomere structure and mitochondrial oxidative metabolism. Genetic deletion of Kdm5a restores histone H3 lysine 4 trimethylation enrichment, reactivates cardiac and metabolic transcriptional programs, improves cardiac function, and prolongs survival. These findings identify KDM5A-mediated chromatin remodeling as a previously unrecognized mechanism of heart failure and highlight KDM5A as a potential therapeutic target.