The Epigenetic Regulator Histone Demethylase KDM5A is Activated and Pathogenic in a Mouse Model of Heart Failure

Heart failure is a complex disease characterized by the dysregulation of gene expression that culminates in cardiac dysfunction. Epigenetic regulators play a critical role in control of transcription and are increasingly implicated in the pathogenesis of heart failure. We recently showed that the histone demethylase KDM5A is reactivated in the heart of human patients and mouse models of heart failure. However, its pathogenic role in heart failure remained unknown. Utilizing a mouse model of heart failure caused by the deletion of the <i>Lmna</i> gene in cardiomyocytes and referred to as LMNA-cardiomyopathy (LMNA-CMP), we show that KDM5A is activated, and expression levels of genes involved in myocyte structure and function, including oxidative phosphorylation (OXPHOS), are suppressed. To determine the pathogenic role of KDM5A in heart failure, the <i>Kdm5a</i> gene was specifically deleted in cardiomyocytes in LMNA-CMP mice ( <i>Myh6-Cre:Lmna</i> ^F/F : <i>Kdm5a</i> ^F/F ). The deletion of the <i>Kdm5a</i> gene improved cardiac function, prolonged survival, attenuated fibrosis, and reduced cell death in LMNA-CMP mice. Transcriptome analysis showed that the deletion of the <i>Kdm5a</i> gene restored the expression of over 1,400 dysregulated genes, including those involved in fatty acid metabolism, myogenesis, and OXPHOS in the <i>Myh6-Cre:Lmna</i> ^F/F : <i>Kdm5a</i> ^F/F mice. Genome-wide profiling of the epigenetic histone mark H3 lysine 4 trimethylation (H3K4me3), the main target of KDM5A, by CUT&RUN assay showed that deletion of the <i>Kdm5a</i> gene partially restored H3K4me3 deposits at loci encoding cardiac transcription factors and metabolic regulators, including <i>Tbx5</i> and <i>Esrrg</i> , with concomitant rescue of their downstream targets. These findings identify KDM5A as a key epigenetic regulator of cardiomyocyte gene expression and uncover a mechanistic role for KDM5A in the pathogenesis of heart failure.