Abstract Body (Do not enter title and authors here): Background: The KDM5 family of histone demethylases regulates chromatin state by removing trimethyl marks from histone H3 lysine 4 (H3K4me3). We previously demonstrated that KDM5 proteins are essential regulators of iPSC-derived cardiomyocyte (CM) maturation, controlling genes involved in oxidative phosphorylation (OXPHOS) and fatty acid oxidation. While KDM5 levels decline with CM maturation, we showed that KDM5A is aberrantly upregulated in human and murine heart failure, including Lamin A/C dilated cardiomyopathy (LMNA-DCM) models.
Objective: To determine the role of KDM5A in LMNA-DCM.
Methods and Results: We utilized a CM-specific Lmna knockout mouse model (Myh6-Cre:Lmna^F/F), which exhibits DCM with contractile dysfunction, increased apoptosis, and a shortened lifespan. KDM5A protein was elevated in these CMs. To assess its functional role, we generated a double-knockout mouse (Myh6-Cre:Lmna^F/F:Kdm5a^F/F) and found that Kdm5a deletion improved cardiac function and extended the survival of LMNA-DCM mice. RNA-seq analysis of wild-type, Myh6-Cre:Lmna^F/F, and Myh6-Cre:Lmna^F/F:Kdm5a^F/F CMs revealed ~6,600 dysregulated genes in LMNA-DCM, with ~1,400 genes rescued upon Kdm5a deletion. Pathway and upstream regulator analyses revealed restoration of OXPHOS and myogenic gene programs, along with suppression of extracellular matrix remodeling and inflammatory signaling. Genome-wide CUT&RUN profiling for H3K4me3 revealed 1,306 dysregulated H3K4me3 peaks, including a global reduction in promoter H3K4me3 enrichment in LMNA-DCM CMs. Deletion of Kdm5a resulted in ~500 H3K4me3 peak gains and additional losses, with ~400 peaks showing reciprocal restoration in H3K4me3 chromatin state. These rescued peaks were enriched near genes responsible for cardiac conduction, sarcomere assembly, and contractility—including key transcription factors such as Esrra, HopX, and Irx4, which also showed restored gene expression. We also identified genes that were rescued independently of H3K4me3 changes, suggesting that KDM5A can repress gene expression via H3K4me3-independent mechanisms. The molecular changes were associated with improved mitochondrial function and reduced activation of intrinsic apoptotic pathways, leading to decreased myocardial apoptosis and fibrosis.
Conclusions: Kdm5a deletion restores gene expression essential for mitochondrial metabolism and sarcomere function, partly via H3K4me3 remodeling, attenuating cardiac dysfunction and increasing survival in LMNA-DCM.