Epigenetic Switch at Atp2a2 and Myh7 Gene Promoters in Pressure Overload-Induced Heart Failure

Angrisano, Tiziana; Schiattarella, Gabriele Giacomo; Keller, Simona; Pironti, Gianluigi; Florio, Ermanno; Magliulo, Fabio; Bottino, Roberta; Pero, Raffaela; Lembo, Francesca; Avvedimento, Enrico V.; Esposito, Giovanni; Trimarco, Bruno; Chiariotti, Lorenzo; Perrino, Cinzia

doi:10.1371/journal.pone.0106024

Cited by 44 publications

(29 citation statements)

References 35 publications

(51 reference statements)

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“…The histone modifications observed post TAC were as follows: dimethylation of H3 at lysine (K) 4 (H3K4), 9 (H3K9) and 36 (H3K36) and trimethylation at lysine 27 (H3K27). Due to these epigenetic changes, the mRNA expression levels of SERCA2a dropped significantly, while β-MHC levels increased (24). The study demonstrated that epigenetic changes occurring in minor cardiomyopathies may cause increased progression towards HF.…”

Section: Heart Failure Epigeneticsmentioning

confidence: 82%

Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions

Kunkel¹,

Chaturvedi²,

Tyagi³

2015

Biomolecular Concepts

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Mitochondrial dysfunction has been reported to underline heart failure, and our earlier report suggests that mitochondrial fusion and fission contributes significantly to volume overload heart failure. Although ample studies highlight mitochondrial dysfunction to be a major cause, studies are lacking to uncover the role of mitochondrial epigenetics, i.e. epigenetic modifications of mtDNA in cardiomyocyte function. Additionally, mitochondrial proteases like calpain and Lon proteases are underexplored. Cardiomyopathies are correlated to mitochondrial damage via increased reactive oxygen species production and free calcium within cardiomyocytes. These abnormalities drive increased proteolytic activity from matrix metalloproteinases and calpains, respectively. These proteases degrade the cytoskeleton of the cardiomyocyte and lead to myocyte death. mtDNA methylation is another factor that can lead to myocyte death by silencing several genes of mitochondria or upregulating the expression of mitochondrial proteases by hypomethylation. Cardiomyocyte resuscitation can occur through mitochondrial interventions by decreasing the proteolytic activity and reverting back the epigenetic changes in the mtDNA which lead to myocyte dysfunction. Epigenetic changes in the mtDNA are triggered by environmental factors like pollution and eating habits with cigarette smoking. An analysis of mitochondrial epigenetics in cigarette-smoking mothers will reveal an underlying novel mechanism leading to mitochondrial dysfunction and eventually heart failure. This review is focused on the mitochondrial dysfunction mechanisms that can be reverted back to resuscitate cardiomyocytes.

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Section: Heart Failure Epigeneticsmentioning

confidence: 82%

Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions

Kunkel¹,

Chaturvedi²,

Tyagi³

2015

Biomolecular Concepts

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“…These results suggest that the expression of fetal genes is induced by mechanical stress and that there is an intimate relationship among cardiomyocyte size, fetal gene expression, and energy metabolism. It remains elusive which molecules regulate cardiomyocyte hypertrophy and the expression of Myh7 and mitochondria-related genes [39,[44][45][46][47][48][49][50], but our novel imaging-analysis pipeline, together with other methods such as single-cell epigenome analysis, will advance our understanding of the molecular network modulating cell size regulation and gene expression at the single-cell level.…”

Section: Discussionmentioning

confidence: 99%

High-throughput single-molecule RNA imaging analysis reveals heterogeneous responses of cardiomyocytes to hemodynamic overload

Satoh

Nomura

Harada

et al. 2019

Journal of Molecular and Cellular Cardiology

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A R T I C L E I N F O Keywords:Heart failure Single-cell spatial analysis Immunostaining Single-molecule fluorescence in situ hybridization A B S T R A C T Background: The heart responds to hemodynamic overload through cardiac hypertrophy and activation of the fetal gene program. However, these changes have not been thoroughly examined in individual cardiomyocytes, and the relation between cardiomyocyte size and fetal gene expression remains elusive. We established a method of high-throughput single-molecule RNA imaging analysis of in vivo cardiomyocytes and determined spatial and temporal changes during the development of heart failure. Methods and results: We applied three novel single-cell analysis methods, namely, single-cell quantitative PCR (sc-qPCR), single-cell RNA sequencing (scRNA-seq), and single-molecule fluorescence in situ hybridization (smFISH). Isolated cardiomyocytes and cross sections from pressure overloaded murine hearts after transverse aortic constriction (TAC) were analyzed at an early hypertrophy stage (2 weeks, TAC2W) and at a late heart failure stage (8 weeks, TAC8W). Expression of myosin heavy chain β (Myh7), a representative fetal gene, was induced in some cardiomyocytes in TAC2W hearts and in more cardiomyocytes in TAC8W hearts. Expression levels of Myh7 varied considerably among cardiomyocytes. Myh7-expressing cardiomyocytes were significantly more abundant in the middle layer, compared with the inner or outer layers of TAC2W hearts, while such spatial differences were not observed in TAC8W hearts. Expression levels of Myh7 were inversely correlated with cardiomyocyte size and expression levels of mitochondria-related genes. Conclusions: We developed a new image-analysis pipeline to allow automated and unbiased quantification of gene expression at the single-cell level and determined the spatial and temporal regulation of heterogenous Myh7 expression in cardiomyocytes after pressure overload.

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“…Alterations in histone methylation have been previously documented in failing human and rodent hearts ( Table 5) (9,137,159,334,388). Using chromatin immunoprecipitation (ChIP) coupled to pyrosequencing, Kaneda and colleagues have demonstrated marked differences in trimethylation for both K4 and K9 residues of histone H3 in both human heart failure and Dahl saltsensitive rat cardiac tissue (159).…”

Section: Histone Methylation and Its Role In Heart Failurementioning

confidence: 99%

Epigenetics of Aberrant Cardiac Wound Healing

Russell‐Hallinan

Watson

Baugh

2018

Comprehensive Physiology

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Remodeling of cardiac tissue architecture is essential for normal organ development and maintaining homeostasis after injury. Injurious insults to the heart, such as hypertension and myocardial infarction, promote cellular responses including stimulation of resident inflammatory cells, activation of endothelial cells and recruitment of immune cells, hypertrophy of cardiomyocytes, and activation of fibroblasts. The physiological goal of this coordinated cellular response is to repair damaged tissue while maintaining or restoring cardiac contractile function. Persistent uncontrolled inflammation, hypertrophy, and fibrosis in the heart due to hyperactive wound healing are detrimental and impair cardiac performance, facilitating the progression to heart failure. Abnormal changes in gene expression promote acquisition of aberrant cellular phenotypes that drive cardiac remodeling. DNA methylation and histone modifications are epigenetic mechanisms that critically regulate chromatin structure and gene expression, and are essential for normal physiology and development. Increasing clinical and experimental evidence suggests that these epigenetic mechanisms are involved in driving aberrant wound healing and the development of heart failure. While most of our knowledge to date is on the heart as a whole, the precise contribution of DNA methylation and histone modifications in regulating aberrant cardiac remodeling at the cellular level is less defined. Therefore, this overview aims to summarize the role of DNA methylation and histone modifications (acetylation and methylation) in heart failure and to comprehensively dissect the role these mechanisms play in regulating the function of cardiomyocytes, fibroblasts, and immune cells in response to injury. © 2018 American Physiological Society. Compr Physiol 8:451-491, 2018.

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Epigenetic Switch at Atp2a2 and Myh7 Gene Promoters in Pressure Overload-Induced Heart Failure

Cited by 44 publications

References 35 publications

Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions

Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions

High-throughput single-molecule RNA imaging analysis reveals heterogeneous responses of cardiomyocytes to hemodynamic overload

Epigenetics of Aberrant Cardiac Wound Healing

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