ArticleCardiovascular research2024
Histone demethylase KDM5 regulates cardiomyocyte maturation by promoting fatty acid oxidation, oxidative phosphorylation, and myofibrillar organization.
Article in Cardiovascular research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 25 citations in OpenAlex.
- Psoralen enhances direct cardiac reprogramming via activating PPARα and driving mitochondrial fission and improves cardiac function after myocardial infarction.Stem cell research & therapy · 2026Article
- KDM5A methylation modulates its genomic demethylase and transcriptional actions.The Journal of biological chemistry · 2026Article
- Histone Modifications in Cardiovascular Disease: Mechanisms and Therapeutic Opportunities.MedComm · 2026Review
- The impact of inflammation, neuromodulation, and gut microbiota on developing cardiac fibrosis and hypertension.Cardiovascular research · 2026Review
- Epigenetics, Modifiers, and Molecular Noise: Rethinking Pathophysiology in Dilated and Hypertrophic Cardiomyopathies.International journal of molecular sciences · 2026Review
- Engineering Smart Biomaterial Interfaces for iPSC-CM Maturation: A Biophysical and Metabolic Reprogramming Approach to Regenerative Cardiac Medicine.International journal of molecular sciences · 2026Review
- Histone lysine demethylases in breast cancer: molecular mechanisms, biological functions, and therapeutic intervention.Molecular cancer · 2025Review
- Cardiomyocyte maturation and proliferation is a flip coin.BMC cardiovascular disorders · 2025Review
- In Vivo Models of Cardiovascular Disease:Biomedicines · 2025Review
- Cardiac intermediary metabolism in heart failure: substrate use, signalling roles and therapeutic targets.Nature reviews. Cardiology · 2025Review
- Metabolic Culture Medium Enhances Maturation of Human iPSC-Derived Cardiomyocytes via Cardiac Troponin I Isoform Induction.International journal of molecular sciences · 2025Article
- Cardiac phenotypes in LMNA mutations.Current opinion in cardiology · 2025Review
- Phenotypic diversity of the LMNA mutations.Current opinion in cardiology · 2025Article
- Bioengineering Approaches to In Vitro Modeling of Genetic and Acquired Cardiac Diseases.Current cardiology reports · 2025Review
- FoxO3 controls cardiomyocyte proliferation and heart regeneration by regulating Sfrp2 expression in postnatal mice.Nature communications · 2025Article
- Clinical trials in-a-dish for cardiovascular medicine.European heart journal · 2024Review
- To Erase or Not to Erase: Non-Canonical Catalytic Functions and Non-Catalytic Functions of Members of Histone Lysine Demethylase Families.International journal of molecular sciences · 2024Review
- Effect of Low-Level Tragus Stimulation on Cardiac Metabolism in Heart Failure with Preserved Ejection Fraction: A Transcriptomics-Based Analysis.International journal of molecular sciences · 2024Article
- Fueling cardiac myocyte proliferation.The journal of cardiovascular aging · 2024Article
- c-JUN is a barrier in hESC to cardiomyocyte transition.Life science alliance · 2023Article
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9 authors at 4 institutions in 1 country.
Funding
Abstract
aimsHuman pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) provide a platform to identify and characterize factors that regulate the maturation of CMs. The transition from an immature foetal to an adult CM state entails coordinated regulation of the expression of genes involved in myofibril formation and oxidative phosphorylation (OXPHOS) among others. Lysine demethylase 5 (KDM5) specifically demethylates H3K4me1/2/3 and has emerged as potential regulators of expression of genes involved in cardiac development and mitochondrial function. The purpose of this study is to determine the role of KDM5 in iPSC-CM maturation. METHODS AND
resultsKDM5A, B, and C proteins were mainly expressed in the early post-natal stages, and their expressions were progressively downregulated in the post-natal CMs and were absent in adult hearts and CMs. In contrast, KDM5 proteins were persistently expressed in the iPSC-CMs up to 60 days after the induction of myogenic differentiation, consistent with the immaturity of these cells. Inhibition of KDM5 by KDM5-C70 -a pan-KDM5 inhibitor, induced differential expression of 2372 genes, including upregulation of genes involved in fatty acid oxidation (FAO), OXPHOS, and myogenesis in the iPSC-CMs. Likewise, genome-wide profiling of H3K4me3 binding sites by the cleavage under targets and release using nuclease assay showed enriched of the H3K4me3 peaks at the promoter regions of genes encoding FAO, OXPHOS, and sarcomere proteins. Consistent with the chromatin and gene expression data, KDM5 inhibition increased the expression of multiple sarcomere proteins and enhanced myofibrillar organization. Furthermore, inhibition of KDM5 increased H3K4me3 deposits at the promoter region of the ESRRA gene and increased its RNA and protein levels. Knockdown of ESRRA in KDM5-C70-treated iPSC-CM suppressed expression of a subset of the KDM5 targets. In conjunction with changes in gene expression, KDM5 inhibition increased oxygen consumption rate and contractility in iPSC-CMs.
conclusionKDM5 inhibition enhances maturation of iPSC-CMs by epigenetically upregulating the expressions of OXPHOS, FAO, and sarcomere genes and enhancing myofibril organization and mitochondrial function.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.