Epigenetic Mechanisms in Heart Failure Pathogenesis

Salvo, Thomas G. Di; Haldar, Saptarsi M.

doi:10.1161/circheartfailure.114.001193

Cited by 30 publications

(23 citation statements)

References 184 publications

(223 reference statements)

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“…30 Epigenetic and gene expression signatures are highly cell type-specific. 31 Therefore, analysis of tissues consisting of complex cell type mixtures may lead to ambiguous results.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the Epigenetic Code of Cardiac Myocyte Transcription

Preißl

Schwaderer

Raulf

et al. 2015

Circulation Research

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Rationale: Epigenetic mechanisms are crucial for cell identity and transcriptional control. The heart consists of different cell types, including cardiac myocytes, endothelial cells, fibroblasts, and others. Therefore, cell type–specific analysis is needed to gain mechanistic insight into the regulation of gene expression in cardiac myocytes. Although cytosolic mRNA represents steady-state levels, nuclear mRNA more closely reflects transcriptional activity. To unravel epigenetic mechanisms of transcriptional control, cell type–specific analysis of nuclear mRNA and epigenetic modifications is crucial. Objective: The aim was to purify cardiac myocyte nuclei from hearts of different species by magnetic- or fluorescent-assisted sorting and to determine the nuclear and cellular RNA expression profiles and epigenetic marks in a cardiac myocyte–specific manner. Methods and Results: Frozen cardiac tissue samples were used to isolate cardiac myocyte nuclei. High sorting purity was confirmed for cardiac myocyte nuclei isolated from mice, rats, and humans. Deep sequencing of nuclear RNA revealed a major fraction of nascent, unspliced RNA in contrast to results obtained from purified cardiac myocytes. Cardiac myocyte nuclear and cellular RNA expression profiles showed differences, especially for metabolic genes. Genome-wide maps of the transcriptional elongation mark H3K36me3 were generated by chromatin-immunoprecipitation. Transcriptome and epigenetic data confirmed the high degree of cardiac myocyte–specificity of our protocol. An integrative analysis of nuclear mRNA and histone mark occurrence indicated a major impact of the chromatin state on transcriptional activity in cardiac myocytes. Conclusions: This study establishes cardiac myocyte–specific sorting of nuclei as a universal method to investigate epigenetic and transcriptional processes in cardiac myocytes of different origins. These data sets provide novel insight into cardiac myocyte transcription.

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“…30 Epigenetic and gene expression signatures are highly cell type-specific. 31 Therefore, analysis of tissues consisting of complex cell type mixtures may lead to ambiguous results.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the Epigenetic Code of Cardiac Myocyte Transcription

Preißl

Schwaderer

Raulf

et al. 2015

Circulation Research

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“…However, both HF phenotypes may distinguish in etiological factors (ischemic/none-ischemic), aging (older vs. younger) and sex presentation, pre-existing co-morbidities (i.e., hypertension, lung and rheumatic disease, diabetes, obesity), as well as predominantly intracellular mechanisms, which are involved in the pathogenesis of cardiac dysfunction. There is not only hypothetically possibilities, but large body of evidence with respect to the tremendous impact of epigenetic modifications (i.e., DNA and histone modifications, ATPdependent chromatin remodeling, and microRNA-related signals and processes) on phenotypic response regarding failing heart and leading to form either HFrEF, or HFpEF [18,19].…”

Section: Short Communicationmentioning

confidence: 99%

“…Various reprogramming of gene expression, including downregulation of the alpha-myosin heavy chain gene, homeobox gene Pitx2c, angiotensin II gene, cardiac troponin T gene, cardiac actin and myosin binding protein C genes, alpha-tropomyosin and myosin light chains genes, sarcoplasmic reticulum Ca2+ ATPase genes, estrogen receptor-alpha, estrogen receptor-beta and reactivation of specific fetal cardiac genes including atrial and brain natriuretic peptides are involved in the phenotypic response in failing heart [19,20].…”

Section: Short Communicationmentioning

confidence: 99%

Epigenetic Modifications the Development of Different Heart Failure Phenotypes

Berezin¹

2016

J Data Mining Genomics Proteomics

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Heart failure (HF) remains a leading cause of death in patient population with known cardiovascular disease. Within last two decades there are evidences regarding decline to determine newel cases with HF with reduced ejection fraction (HFrEF) in developed countries, whereas the frequency of newly-diagnosed HF with preserved ejection fraction (HFpEF) exhibits dramatically rise. Epigenetic modification is considered a modification of the non-DNA sequences related heritable changes in gene expression of target cells. Epigenetic modifications affect several molecular mechanisms, i.e., DNA methylation and deactylation, ATP-dependent chromatin remodeling, histone modifications, and microRNA regulation. The short commentary is clarified the implication of epigenetic modifications in development of different HF phenotypes.Keywords: Heart failure; Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Epigenetics Short CommunicationHeart failure (HF) is a sufficient medical problem and social burden that associates with increased morbidity/mortality rate and disability rate in the developed countries [1]. Within last decades there is progressively decrease of prevalence of HF with reduced left ventricular ejection fraction (HFrEF) [2]. In opposite, the frequency of newly-diagnosed HF with preserved left ventricular ejection fraction (HFpEF) appears to be raised [3]. These changes in presentation of HF phenotypes might relate to advance in contemporary of HF medical care [4], impact of age-related comorbidities and socioeconomic status [5][6][7][8]. Despite the implementation in routine clinical practice modern pharmacological strategy and none-drug therapy including implanted devices for mechanical support and pacing [8][9][10], the clinical outcomes in subjects with HFrEF and HFpEF remain similar [11].

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“…Epigenetics strictly speaking refers to any aspect of gene expression regulation not dependent on changes in the DNA primary nucleotide sequence [16]. As such, epigenetics subsumes the aggregate effects of i) signals transduced by transcription factors and other DNA and RNA binding proteins, ii) interactions of multiple RNA species (e.g., long noncoding RNA, miRNAs, mRNAs), iii) localization and activity of multicomponent regulatory chromatin binding complexes (e.g., Mediator, the Polycomb repressive complexes), iv) key enzyme activities (e.g., RNA polymerase II), v) activation or inactivation of DNA regulatory sequences (e.g., enhancers, silencers) and vi) chromatin accessibility determined by both local and long-range chromatin conformations [16]. Preclinical and clinical studies of epigenetic approaches to heart failure therapeutics to date have targeted the left ventricular, not right ventricular failure.…”

Section: Epigenomic Modulationmentioning

confidence: 99%

Evolving targeted therapies for right ventricular failure

Salvo¹

2015

Expert Opinion on Biological Therapy

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Strategies for adult right ventricular regeneration will require a more holistic approach than strategies for adult left ventricular failure. Instances of right ventricular failure requiring global reconstitution of right ventricular myocardium, attractive approaches include: i) myocardial patches seeded with cardiac fibroblasts reprogrammed into cardiomyocytes in vivo by small molecules, miRNAs or other epigenetic modifiers; and ii) administration of miRNAs, lncRNAs or small molecules by non-viral vector delivery systems targeted to fibroblasts (e.g., episomes) to stimulate in vivo reprogramming of fibroblasts into cardiomyocytes. For selected heritable genetic myocardial diseases, genomic editing affords exciting opportunities for allele-specific silencing by site-specific directed silencing, mutagenesis or gene excision. Genomic editing by adoptive gene transfer affords similarly exciting opportunities for restoration of myocardial gene expression.

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Epigenetic Mechanisms in Heart Failure Pathogenesis

Cited by 30 publications

References 184 publications

Deciphering the Epigenetic Code of Cardiac Myocyte Transcription

Deciphering the Epigenetic Code of Cardiac Myocyte Transcription

Epigenetic Modifications the Development of Different Heart Failure Phenotypes

Evolving targeted therapies for right ventricular failure

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