{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE309nnn/GSE309726/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE309726"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Genetic Deletion of Histone Lysine Demethylase KDM5A in Cardiomyocytes Attenuates LMNA-Dilated Cardiomyopathy","description":"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.","dates":{"publication":"2026/09/30"},"accession":"GSE309726","cross_references":{"GSM":["GSM9278029","GSM9278028","GSM9278027","GSM9278037","GSM9278026","GSM9278025","GSM9278036","GSM9278024","GSM9278035","GSM9278034","GSM9278023","GSM9278033","GSM9278032","GSM9278031","GSM9278030"],"GPL":["30172"],"GSE":["309726"],"taxon":["Mus musculus"]}}