Targeted DNA Methylation Profiling of Human Cardiac Tissue Reveals Novel Epigenetic Traits and Gene Deregulation Across Different Heart Failure Patient Subtypes

Glezeva, Nadezhda; Moran, Bruce; Collier, Patrick; Moravec, Christine S.; Phelan, Dermot; Donnellan, Eoin; Russell‐Hallinan, Adam; O’Connor, Darran P.; Gallagher, William M.; Gallagher, Joe; McDonald, Ken; Ledwidge, Mark; Baugh, John; Das, Sudipto; Watson, Chris

doi:10.1161/circheartfailure.118.005765

Cited by 77 publications

(77 citation statements)

References 17 publications

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“…Abnormal regulation of genes and/or proteins involved in sarcomere organization, expression of cardiac hormones and proto‐oncogenes, and extracellular matrix remodelling that directly influences cardiac function and structure has been described in numerous studies of DCM and heart failure . Moreover, it was recently suggested that epigenetic mechanisms play a pivotal role in the regulation of cardiac gene expression patterns during the progression of cardiac hypertrophy and failure . In the present study, nuclear DNA methylation in cardiomyocytes was found to correlate significantly with parameters of LV remodelling (LV dilatation and LV hypertrophy) and LV dysfunction.…”

Section: Discussionsupporting

confidence: 59%

“…Several studies have investigated genome‐wide DNA methylation in failing hearts. Movassagh et al reported that DNA methylation is altered in human failing hearts, and this was confirmed in subsequent studies . However, all of those studies assessed DNA methylation biochemically using immunoprecipitation chips, where DNA from not only cardiomyocytes but also other cell types within the myocardium was analysed without distinguishing among them.…”

Section: Discussionmentioning

confidence: 89%

“…Recent studies have shown that distinct epigenomic DNA methylation patterns are present at important DNA elements within the cardiac genome in human end‐stage cardiomyopathy and that differential DNA methylation correlates with differential expression of angiogenic factors in human heart failure . Subsequent studies also using human cardiac tissue revealed differences in methylation of genes involved in pathways related to heart disease, which may provide an opportunity for differential diagnosis of heart failure . Gilsbach et al provided information on how DNA methylation patterns change during developmental and pathological remodelling; interestingly, in a pressure overload model of heart failure, the DNMT3A‐catalyzed patterns of DNA methylation detected in isolated cardiomyocytes were similar to those seen during development.…”

Section: Introductionmentioning

confidence: 99%

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In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study

et al. 2020

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Aims Although distinct DNA methylation patterns have been reported, its localization and roles remain to be defined in heart failure. We investigated the cellular and subcellular localization of DNA methylation and its pathophysiological significance in human failing hearts. Methods and results Using left ventricular (LV) endomyocardial biopsy specimens from 75 patients with dilated cardiomyopathy (DCM; age: 58 ± 14 years old, %female: 32%) and 20 patients without heart failure (controls; age: 56 ± 17 years old, %female: 45%), we performed immunohistochemistry and immunoelectron microscopy for methylated DNA, 5methylcytosine (5-mC). We next investigated possible relations of the incidence of 5-mC-positive (%5-mC + ) cardiomyocytes with clinicopathological parameters. Immunopositivity for 5-mC was detected in the cardiomyocytes and other cell types. The %5-mC + cardiomyocytes was significantly greater in DCM hearts than in controls (57 ± 13% in DCM vs. 25 ± 12% in controls, P < 0.0001). The localization of 5-mC immunopositivity in cardiomyocyte nuclei coincided well with that of heterochromatin, as confirmed by immunoelectron microscopy. Substantial DNA methylation was also observed in interstitial noncardiomyocytes, but the incidences did not differ between control and DCM hearts (39 ± 7.9% in DCM vs. 41 ± 10% in controls, P = 0.4099). In DCM patients, the %5-mC + cardiomyocytes showed a significant inverse correlation with LV functional parameters such as heart rate (r = 0.2391, P = 0.0388), end-diastolic pressure (r = 0.2397, P = 0.0397), and ejection fraction (r = À0.2917, P = 0.0111) and a positive correlation with LV dilatation (volume index at diastole; r = 0.2442, P = 0.0347; and volume index at systole; r = 0.3136, P = 0.0062) and LV hypertrophy (mass index; r = 0.2287, P = 0.0484)-that is, LV remodelling parameters. No significant correlations between DNA methylation and the histological parameters of the biopsies, including cardiomyocyte hypertrophy, fibrosis, and inflammatory cell infiltration, were noted. Conclusions The present study revealed increased nuclear DNA methylation in cardiomyocytes, but not other cell types, from DCM hearts, with predominant localization in the heterochromatin. Its significant relations with LV functional and remodelling parameters imply a pathophysiological significance of DNA methylation in heart failure.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study

et al. 2020

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“…In the gene body (c), positive association has been demonstrated between increased methylation and transcriptional activation and elongation. Removal of 5MeC from the gene body therefore is associated with transcriptional repression aetiologies [40][41][42][43][44][45][46]. Further to the first reported alterations in DNA methylation in patients with end-stage HF [40,41], several major studies have specifically focussed on profiling DNA methylation changes in dilated cardiomyopathy (DCM) [42][43][44]47].…”

Section: Dna Methylation In Heart Failurementioning

confidence: 99%

“…In the context of ischaemic cardiomyopathy (ICM), differential DNA methylation has been linked with differences in gene expression compared to non-ischaemic cardiomyopathy, indicating that ICM correlates with relative hypermethylation of promoter-associated CGIs associated with repression of genes involved in oxidative metabolism [45]. , with significantly altered levels consistent with the direction of methylation identified in the particular HF patient sub-group [46]. There is also increasing evidence suggesting that 5hMeC generated by the action of TETs may play a functional role in remodelling processes in the heart [48,49].…”

Section: Dna Methylation In Heart Failurementioning

confidence: 99%

Epigenetic Regulation of Endothelial Cell Function by Nucleic Acid Methylation in Cardiac Homeostasis and Disease

Russell‐Hallinan

Watson

O'Dwyer

et al. 2020

Cardiovasc Drugs Ther

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Pathological remodelling of the myocardium, including inflammation, fibrosis and hypertrophy, in response to acute or chronic injury is central in the development and progression of heart failure (HF). While both resident and infiltrating cardiac cells are implicated in these pathophysiological processes, recent evidence has suggested that endothelial cells (ECs) may be the principal cell type responsible for orchestrating pathological changes in the failing heart. Epigenetic modification of nucleic acids, including DNA, and more recently RNA, by methylation is essential for physiological development due to their critical regulation of cellular gene expression. As accumulating evidence has highlighted altered patterns of DNA and RNA methylation in HF at both the global and individual gene levels, much effort has been directed towards defining the precise role of such cell-specific epigenetic changes in the context of HF. Considering the increasingly apparent crucial role that ECs play in cardiac homeostasis and disease, this article will specifically focus on nucleic acid methylation (both DNA and RNA) in the failing heart, emphasising the key influence of these epigenetic mechanisms in governing EC function. This review summarises current understanding of DNA and RNA methylation alterations in HF, along with their specific role in regulating EC function in response to stress (e.g. hyperglycaemia, hypoxia). Improved appreciation of this important research area will aid in further implicating dysfunctional ECs in HF pathogenesis, whilst informing development of EC-targeted strategies and advancing potential translation of epigenetic-based therapies for specific targeting of pathological cardiac remodelling in HF.

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Current Preclinical Applications of Pharmaco-Epigenetics in Cardiovascular Diseases

Papulino,

Chianese,

Scisciola

et al. 2023

Epigenetics and Human Health

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Targeted DNA Methylation Profiling of Human Cardiac Tissue Reveals Novel Epigenetic Traits and Gene Deregulation Across Different Heart Failure Patient Subtypes

Abstract: Targeted DNA methylation profiling of human cardiac tissue reveals novel epigenetic traits and gene deregulation across different Heart Failure patient sub-types Glezeva DNA methylation profiling of Heart Failure

Cited by 77 publications

References 17 publications

In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study

In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study

Epigenetic Regulation of Endothelial Cell Function by Nucleic Acid Methylation in Cardiac Homeostasis and Disease

Current Preclinical Applications of Pharmaco-Epigenetics in Cardiovascular Diseases

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