Role of Brahma-Related Gene 1 (Brg1) in Heart Disease
Heart disease remains a leading global cause of mortality, necessitating deeper exploration of molecular mechanisms driving its pathogenesis. Among emerging therapeutic targets, Brahma-related gene 1 (Brg1), a catalytic ATPase subunit of the SWI/SNF chromatin-remodeling complex, has garnered attention for its multifaceted roles in cardiac development and disease progression. This article synthesizes current evidence on Brg1’s structural features, regulatory mechanisms, and contributions to specific cardiac pathologies, including hypertrophy, aortic aneurysms, heart failure, diabetic cardiomyopathy, and ischemia-reperfusion injury.
Structural and Functional Domains of Brg1
Brg1 spans over 1,600 amino acids and harbors distinct domains essential for its chromatin-remodeling activity. The N-terminal QLQ domain facilitates protein-protein interactions, potentially stabilizing conformational structures. Adjacent to this, the HSA domain associates with helicases and DNA-binding proteins. The BRK domain mediates transcriptional regulation by interacting with chromatin modifiers like DEAD/DEAH helicases. The AT-hook motif binds DNA, while the bromodomain recognizes acetylated lysine residues on histones H3 and H4, enabling recruitment to acetylated chromatin regions. These domains collectively enable Brg1 to orchestrate transcriptional activation or repression by forming dynamic complexes with histone-modifying enzymes, transcription factors, or repressors such as HDACs.
Brg1 in Cardiac Hypertrophy
Pathological cardiac hypertrophy, characterized by cardiomyocyte enlargement and fibrosis, is tightly linked to Brg1 reactivation in stressed adult hearts. Brg1 interacts with forkhead box protein M1 (FoxM1) to drive hypertrophic gene programs. For instance, Brg1 recruits HDACs and poly (ADP-ribose) polymerase (PARP) to the myosin heavy chain (MHC) promoter, shifting expression from the adult α-MHC isoform to the fetal β-MHC isoform, a hallmark of hypertrophy. Genetic ablation of Brg1 blocks this transition, attenuating hypertrophy. Similarly, Brg1 knockdown disrupts endothelin-1 promoter recruitment of histone H3K4 methylation complexes, further mitigating hypertrophic responses. These findings highlight Brg1 as a central node in stress-induced transcriptional reprogramming.
Brg1 in Aortic Aneurysm Pathogenesis
Aortic aneurysms involve pathological smooth muscle cell (SMC) phenotypic switching, inflammation, and extracellular matrix degradation. Brg1 regulates SMC differentiation by binding promoters of contractile genes like α-actin and SM22α, maintaining their repression. Clinically, Brg1 expression is elevated in thoracic aortic aneurysm patients compared to healthy individuals. Mechanistically, Brg1 interacts with long non-coding RNA HIF1A-AS1 to destabilize SMC contractile phenotypes. Additionally, Brg1 is recruited to the matrix metalloproteinase 2 (MMP2) promoter, upregulating MMP2 and MMP9 expression, which degrade collagen and elastin, exacerbating vascular remodeling. These actions position Brg1 as a critical mediator of SMC dysfunction in aneurysms.
Brg1 in Heart Failure
Heart failure often arises from dysregulated trabeculation during development or adverse remodeling in adulthood. Brg1 interacts with cardiac transcription factors like Tbx5, Tbx20, and NKX2-5 to balance trabecular growth. Disruption of this equilibrium causes myocardial over- or underdevelopment. In adult hearts, Brg1 represses ADAMTS1, a protease inhibiting trabeculation, by binding its promoter. Brg1/Brm double-knockout mice exhibit dilated cardiomyopathy and heart failure, underscoring its role in maintaining cardiac structure. Furthermore, Brg1 modulates fetal gene re-expression (e.g., β-MHC) during failure, suggesting therapeutic potential through targeted inhibition.
Brg1 in Diabetic Cardiomyopathy
Diabetic cardiomyopathy involves oxidative stress, inflammation, and endothelial dysfunction. Brg1 exacerbates endothelial injury by binding promoters of adhesion molecules like ICAM-1 and VCAM-1, promoting leukocyte infiltration. Hyperglycemia impairs nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated recruitment of Brg1 to antioxidant gene promoters (e.g., heme oxygenase-1 [HO-1]), reducing cytoprotective responses. Conversely, adiponectin, an adipokine with anti-hypertrophic effects, enhances Brg1-Nrf2 interactions, restoring HO-1 and STAT3 expression. This dual role underscores context-dependent regulation of Brg1 in diabetic hearts.
Brg1 in Myocardial Ischemia-Reperfusion Injury (MIRI)
Ischemia-reperfusion injury involves oxidative damage and neutrophil infiltration. In zebrafish, Brg1 collaborates with Dnmt3ab to suppress cdkn1c via promoter methylation, enabling cardiomyocyte proliferation post-injury. In mammals, Brg1 facilitates Nrf2-dependent Z-DNA formation, recruiting RNA polymerase II to enhance HO-1 and STAT3 transcription, thereby reducing oxidative stress. Paradoxically, Brg1 also interacts with H3K9 demethylase 3A (KDM3A) at the NADPH oxidase (NOX) promoter, activating NOX and exacerbating oxidative damage. Brg1 deficiency reduces neutrophil recruitment by downregulating podocalyxin-like protein 1 (PODXL), attenuating infarct size. These conflicting roles highlight the need for cell-type and context-specific therapeutic strategies.
Therapeutic Implications and Future Directions
Brg1’s involvement in diverse cardiac pathologies positions it as a promising therapeutic target. Inhibiting Brg1 could mitigate hypertrophy, aneurysm progression, and MIRI, while enhancing its activity might promote regeneration or antioxidant responses. However, challenges remain:
- Dual Roles: Brg1’s context-dependent effects (e.g., pro-survival vs. pro-oxidant) necessitate precise targeting to avoid off-pathway consequences.
- Complex Interactions: Brg1 functions within multi-protein complexes; disrupting specific interactions (e.g., with HDACs vs. KDM3A) requires highly selective inhibitors.
- Temporal Regulation: Reactivating Brg1 during development versus inhibiting it in disease states demands temporally controlled delivery systems.
Future studies should clarify Brg1’s isoform-specific functions, epigenetic partners, and downstream effectors across cardiac cell types. Clinical trials exploring Brg1 modulators, combined with biomarkers for patient stratification, could accelerate translation.
Conclusion
Brg1 exemplifies the complexity of chromatin remodeling in heart disease. Its ability to integrate epigenetic, transcriptional, and post-translational signals underscores its centrality in cardiac pathophysiology. While significant progress has been made in delineating its roles in hypertrophy, aneurysms, and ischemia-reperfusion injury, resolving its dualistic functions remains critical. By leveraging advances in gene editing and small-molecule inhibitors, targeting Brg1 could herald novel therapies for heart disease, ultimately reducing its global burden.
doi.org/10.1097/CM9.0000000000001480
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