Epigenetic and chromatin remodeling mechanisms across cardiomyopathies: a comprehensive review

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  Fig. 1. Flowchart of literature search and study selection. Flowchart summarizing the literature search and article selection process used for this review. A total of 987 records were identified through PubMed and Google Scholar using keywords related to chromatin remodeling, epigenetics, histone modifications, and cardiomyopathies. At initial selection 840 articles were processed. After screening titles, abstracts, and full-text relevance, 531 records were excluded because they were editorials, insufficient focus on cardiomyopathies or chromatin remodeling, news articles, or opinion pieces without original data, non-peer-reviewed sources. Finally, 309 peer-reviewed studies were included in the review

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  Fig. 2. Major chromatin remodeling complex families in cardiac tissue. Four ATP-dependent chromatin remodeling families regulate cardiac gene expression. SWI/SNF (BAF) complexes, containing BRG1/BRM and cardiac-specific subunits such as BAF60c, enable nucleosome sliding and gene activation. NuRD couples CHD4 remodeling with HDAC1/2 deacetylation to enforce repression and maintain sarcomere identity. PRC2 (EZH2/EZH1) deposits H3K27me3 to silence developmental and metabolic genes. ISWI and CHD remodelers regulate nucleosome spacing and chromatin assembly. Together, these complexes transition chromatin between closed and accessible states, and their dysregulation in cardiomyopathies drives pathological transcriptional programs.

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  Fig. 3. Chromatin remodeling alterations across cardiomyopathy subtypes. Cardiomyopathy subtypes display distinct chromatin remodeling signatures underlying their phenotypes. In DCM, reduced BAF250a, heightened EZH2 activity, CHD4 dysregulation, and BRG1 redistribution suppress metabolic genes. HCM involves BRG1 reactivation, HDAC5/HDAC2 imbalance, elevated p300, and H3K27ac changes driving the α- to β-MHC isoform switch. AC is characterized by Wnt/β-catenin–driven activation of BRG1/BAF, increased accessibility at adipogenic loci, and altered HDAC control of Cx43 promoting fibrofatty replacement. RCM remains poorly defined, with evidence for cTnI-SMYD1 interactions and histone changes at the PDE4d locus. Across subtypes, shared mechanisms include fetal gene reactivation (BRG1-mediated MHC switching), EZH2-driven metabolic remodeling, loss of cardiomyocyte identity via CHD4/NuRD dysfunction, and BRG1/BAF-dependent fibrotic activation through TGF-β signaling.

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  Fig. 4. Integrated epigenetic networks in cardiac gene regulation. Chromatin remodelers act within coordinated epigenetic networks involving DNA methylation, histone modifications, transcription factors, and non-coding RNAs. DNMT-mediated DNA methylation recruits MBD proteins and the NuRD complex to establish repression. NuRD couples CHD4 remodeling with HDAC1/2 deacetylation. Cardiac TFs (GATA4, NKX2.5, MEF2C, TBX5) direct remodelers to target loci; e.g., BAF60c interacts with GATA4/TBX5 to recruit BAF to enhancers. Histone-modifying enzymes add or remove activating (H3K27ac, H3K4me3) or repressive (H3K27me3, H3K9me3) marks in concert with remodelers. lncRNAs such as Fendrr and Chaer guide PRC2 and BAF to specific loci. A key example is BRG1-dependent recruitment of G9a/GLP and subsequently DNMT3a at the Myh6 locus, depositing H3K9me2 and DNA methylation to silence α-MHC during pathological remodeling. Ac= Acetylation (Green Circle, Activating); mC- DNA Methylation (Yellow Circle, Repressive); H384me3 = Histone Methylation (Purple Square, Activating); H3K9me3, H3K27me3, H3K9me2 = Histone Methylation (Red-Orange Hexagon/ Triangle, Repressive), DNMTs = DNA Methyltransferases; MBD=…

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  Fig. 5. Therapeutic targeting of chromatin remodeling in cardiomyopathies. Multiple therapeutic strategies are being developed to target pathological chromatin remodeling in cardiomyopathies. Alternatively, context-dependent inhibition strategies that preferentially target disease-associated PRC2 complexes while preserving homeostatic PRC2 functions represent an aspirational goal for future drug development [32, 295].