BRG1 is a biomarker of hypertrophic cardiomyopathy in human heart specimens

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetic disease of the sarcomere that causes otherwise unexplained cardiac hypertrophy and is associated with sudden death. While previous studies showed the role of the epigenetic modifier Brg1 in mouse models of HCM, additional work is needed to identify its role in humans. We tested the hypothesis that BRG1 expression is increased in periods of cardiac remodeling during fetal growth and in development of HCM. We employed immunohistochemical staining to evaluate protein expression of BRG1 in 796 human cardiac specimens (81 from patients with HCM) and describe elevated BRG1 expression in human fetal hearts in early development. In addition, we not only demonstrate increased expression of BRG1 in HCM, but we also show that other diseases that lead to heart failure have similar BRG1 expression to healthy controls. Inhibition of BRG1 in human induced pluripotent stem cell-derived cardiomyocytes significantly decreases MYH7 and increases MYH6, suggesting a regulatory role for BRG1 in the pathological imbalance of the two myosin heavy chain isoforms in human HCM. These data are the first demonstration of BRG1 as a specific biomarker for human HCM and provide foundation for future studies of epigenetics in human cardiac disease.

Superfamily II helicases: the potential therapeutic target for cardiovascular diseases

“…Immunohistochemical staining from 796 human cardiac specimens found that Brg1 expression significantly increased in patients with HCM compared to other causes of ventricular hypertrophy and dilated cardiomyopathy (DCM). In vitro, inhibition of Brg1 significantly decreased cardiomyocyte β-MHC expression and increased α- MHC expression ( 73 ), consistent with findings reported by Hang et al ( 72 ). However, the evidence of Brg1 as the causative gene for HCM is remained limited.…”

“…However, the reactivation of fetal genes may induce cardiac pathologic hypertrophy ( 72 ). Moreover, Brg1 has been reported to be associated with hypertrophic cardiomyopathy (HCM) and heart failure (HF) pathological remodeling mechanisms ( 73 , 74 ). Brg1 reactivated in the adult myocardium, in this setting, may promote pathology and adverse remodeling rather than the regenerative response.…”

Single-nucleus RNA/ATAC-seq in early-stage HCM models predicts SWI/SNF-activation in mutant-myocytes, and allele-specific differences in fibroblasts

“…BRG1 ( Smarca4 ) is silenced in adult cardiac myocytes, but reactivated by cardiac stresses such as increased afterload resulting from TAC (transverse aortic constriction) or hypertension 54 , leading to the formation of SWI/SNF complexes that remodel chromatin, activate the fetal cardiac gene program 54 and promote cardiac remodeling. An immunohistochemical study of BRG1 expression in human heart tissue revealed higher BRG1 expression in HCM than DCM, and other causes of LVH 55 . Our regulon analysis predicted Smarca4 regulon activation in mutant ventricular cardiomyocytes but not in control cardiomyoctes ( Fig 2h ).…”

“…An immunohistochemical study of BRG1 expression in human heart tissue revealed higher BRG1 expression in HCM than DCM, and other causes of LVH 55 . Our regulon analysis predicted Smarca4 regulon activation in mutant ventricular cardiomyocytes but not in control cardiomyoctes (Fig 2h).…”

Non-Random Enrichment of Single-Nucleotide Polymorphisms Associated with Clopidogrel Resistance within Risk Loci Linked to the Severity of Underlying Cardiovascular Diseases: The Role of Admixture

“…BRG1 is part of the SWI/SNF complex, with ATPase and helicase activity, that participates in chromatin remodeling. Although the underlying pathway related to BRG1 is not yet fully elucidated, a recent human in vitro study demonstrated that BRG1 is highly expressed in hypertrophic cardiomyopathy and can alter myosin expression [ 54 ]. The rs9349379 SNP in the PHACTR1 gene is an eQTL that has been found to be associated with CAD risk.…”