Genetic Deletion of Histone Lysine Demethylase KDM5A in Cardiomyocytes Attenuates LMNA-Dilated Cardiomyopathy

ABSTRACT: Mutations in the LMNA gene, cause of dilated cardiomyopathy (LMNA-DCM); a progressive cardiac disorder currently lacking targeted therapeutic interventions. While the genetic basis is established, the epigenetic mechanisms driving LMNA-DCM pathogenesis remain poorly understood. In this study, we identify the histone demethylase KDM5A as an epigenetic regulator in the pathogenesis of LMNA-DCM. Using a cardiomyocyte-specific Lmna knockout mouse model (Myh6-Cre:LmnaF/F), we observed upregulation of KDM5A, which coincided with the downregulation of genes involved in myocardial contractility, mitochondrial bioenergetics, and oxidative phosphorylation (OXPHOS). We show that cardiomyocyte-specific deletion of Kdm5a in the LMNA-DCM background (Myh6-Cre:LmnaF/F:Kdm5aF/F) led to improved cardiac function, extended survival, and marked reductions in fibrosis and apoptosis. Transcriptomic analysis of cardiomyocytes from wild-type, Myh6-Cre:LmnaF/F, and Myh6-Cre:LmnaF/F:Kdm5aF/F mice revealed restoration of expression in over 1,400 genes, including pathways regulating fatty acid metabolism, myogenesis, and OXPHOS in the Myh6-Cre:LmnaF/F:Kdm5aF/F. Corresponding genome-wide profiling using CUT&RUN across the three groups showed reduced promoter-associated H3K4me3 in Myh6-Cre:LmnaF/F hearts, which was partially restored by Kdm5a deletion. Notably, H3K4me3 levels were reinstated at loci encoding cardiac transcription factors and metabolic regulators, in Myh6-Cre:LmnaF/F:Kdm5aF/F CM. These epigenetic and transcriptional changes were accompanied by decreased cardiomyocyte death and fibrosis. Overall, our findings position KDM5A as an epigenetic mediator of gene dysregulation in LMNA-DCM and provide mechanistic insights in the pathogenesis of the disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE309726 | GEO | 2026/09/30

REPOSITORIES: GEO