Genome-Wide DNA Methylation Encodes Cardiac Transcriptional Reprogramming in Human Ischemic Heart Failure [DNA Methylation]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE109097 | GEO | 2018/08/22
REPOSITORIES: GEO
Similar Datasets
Project description:Background – Epigenetic alterations are stable modifications to chromatin structure that occur in response to environmental cues such as hypoxia or altered nutrient delivery. DNA methylation is a well-established and dynamic DNA modification that contributes to the regulation of gene expression. In the current study, we test the hypothesize that ischemic heart failure is defined by a distinct signature of DNA methylation that corresponds with altered expression of genes involved in cardiac ventricular dysfunction. Methods and Results – Using a methylation array, we quantified genome-wide DNA methylation of endomyocardial samples acquired from patients with ischemic (n = 6) or non-ischemic (n = 5) heart failure. RNA-sequencing analysis was performed in the same samples to identify transcriptomic changes (Fold Change > 1.5, Q < 0.05, FPKM > 2) associated with differential methylation (|Percent Change| > 5%, p < 0.05). Of the promoter-associated CpG Islands, which are well-established regions of negative transcriptional regulation, we identified a signature of robust hypermethylation. The methylation changes linked to significantly decreased transcripts included key fatty acid metabolic regulators (e.g. KLF15, AGPAT9, APOA1, and MXD4). Among the few hypomethylated and induced genes was PFKFB3, which encodes for the rate-limiting enzyme of glycolysis. Gene set enrichment analysis identified TGFβ as a nodal upstream regulator of the methylation changes, potentially supporting a role of DNA methylation in the increased fibrosis and apoptosis that accompanies ischemic heart failure. Conclusions – Our data identify that the DNA methylation signature recapitulates the pathologic hallmarks of ischemic heart failure. Furthermore, we show that differential DNA methylation of CpG islands within the promoter depict alterations in metabolic substrate utilization known to occur in ischemic heart failure, and may govern a return to the fetal-like metabolic program.
2018-08-22 | GSE109096 | GEO
Project description:Background – Epigenetic alterations are stable modifications to chromatin structure that occur in response to environmental cues such as hypoxia or altered nutrient delivery. DNA methylation is a well-established and dynamic DNA modification that contributes to the regulation of gene expression. In the current study, we test the hypothesize that ischemic heart failure is defined by a distinct signature of DNA methylation that corresponds with altered expression of genes involved in cardiac ventricular dysfunction. Methods and Results – Using a methylation array, we quantified genome-wide DNA methylation of endomyocardial samples acquired from patients with ischemic (n = 6) or non-ischemic (n = 5) heart failure. RNA-sequencing analysis was performed in the same samples to identify transcriptomic changes (Fold Change > 1.5, Q < 0.05, FPKM > 2) associated with differential methylation (|Percent Change| > 5%, p < 0.05). Of the promoter-associated CpG Islands, which are well-established regions of negative transcriptional regulation, we identified a signature of robust hypermethylation. The methylation changes linked to significantly decreased transcripts included key fatty acid metabolic regulators (e.g. KLF15, AGPAT9, APOA1, and MXD4). Among the few hypomethylated and induced genes was PFKFB3, which encodes for the rate-limiting enzyme of glycolysis. Gene set enrichment analysis identified TGFβ as a nodal upstream regulator of the methylation changes, potentially supporting a role of DNA methylation in the increased fibrosis and apoptosis that accompanies ischemic heart failure. Conclusions – Our data identify that the DNA methylation signature recapitulates the pathologic hallmarks of ischemic heart failure. Furthermore, we show that differential DNA methylation of CpG islands within the promoter depict alterations in metabolic substrate utilization known to occur in ischemic heart failure, and may govern a return to the fetal-like metabolic program.
2018-08-22 | GSE108157 | GEO
Project description:Genome-Wide DNA Methylation Encodes Cardiac Transcriptional Reprogramming in Human Ischemic Heart Failure [DNA Methylation]
| PRJNA429637 | ENA
Project description:Genome-Wide DNA Methylation Encodes Cardiac Transcriptional Reprogramming in Human Ischemic Heart Failure [DNA Methylation]
| PRJNA429632 | ENA
Project description:Ischemic cardiomyopathy (ICM) is the clinical endpoint of coronary heart disease and a leading cause of heart failure. Despite growing demands to develop personalized approaches to treat ICM, progress is limited by inadequate knowledge of its pathogenesis. Since epigenetics has been implicated in the development of other chronic diseases, the current study was designed to determine whether transcriptional and/or epigenetic changes are sufficient to distinguish ICM from other etiologies of heart failure. Specifically, we hypothesize that genome-wide DNA methylation encodes transcriptional reprogramming in ICM. RNA-sequencing analysis was performed on human ischemic left ventricular tissue obtained from patients with end-stage heart failure, which enriched known targets of the polycomb methyltransferase EZH2 compared to non-ischemic hearts. Combined RNA sequencing and genome-wide DNA methylation analysis revealed a robust gene expression pattern consistent with suppression of oxidative metabolism, induced anaerobic glycolysis, and altered cellular remodeling. Lastly, KLF15 was identified as a putative upstream regulator of metabolic gene expression that was itself regulated by EZH2 in a SET domain-dependent manner. Our observations therefore define a novel role of DNA methylation in the metabolic reprogramming of ICM. Furthermore, we identify EZH2 as an epigenetic regulator of KLF15 along with DNA hypermethylation, and we propose a novel mechanism through which coronary heart disease reprograms the expression of both intermediate enzymes and upstream regulators of cardiac metabolism such as KLF15.
| S-EPMC6515060 | biostudies-literature
Project description:Increased morbidity and mortality associated with post-ischemic heart failure (HF) in diabetic patients underscore the need for a better understanding of the underlying molecular events. Indeed, effective HF therapy in diabetic patients requires a complex strategy encompassing the development of improved diagnostic and prognostic markers and innovative pharmacological approaches. Whole mRNAs expression was measured in the heart of patients with heart failure (HF) with or without concomitant Type 2 diabetes mellitus (T2DM) and compared it to control non-failing hearts. We identified distinct genes modulated in HF patients compared to controls, as well as to T2DM HF patients compared to not diabetic HF patients. Our study included left ventricle (LV) cardiac biopsies taken from the vital, non-infarcted zone (remote zone) derived from patients affected by dilated hypokinetic post-ischemic cardiomyopathy, undergoing surgical ventricular restoration procedure. Inclusion criteria for diabetic were: GLICEMIA: >=126 mg/dl, previous T2DM diagnosis or anti-diabetic therapy, while for non diabetic: GLICEMIA: <100 mg/dl and HbA1c: n.v. 4.8-6.0%. Moreover, HF patients were matched for End Systolic Volume (ESV), Ejection fraction (LVEF), Age, Sex, Ethnic distribution, Smoke habits, Hypertension, Glomerular filtration rate (GFR), Body Mass Index (BMI). Genes expression was assessed by Affymetrix GeneChips Human Gene 1.0 ST array, using total RNA extracted from 7 T2DM HF patients, 12 non-T2DM HF patients and 5 controls.
2012-03-21 | E-GEOD-26887 | biostudies-arrayexpress
Project description:LCMS files from tryptic digests of ~1-4 mg piece of heart ventricular tissue from human with ischemic heart failure and non-failing controls.
Specimen number correspond to .raw files as follows:
Ischemic Heart failure -
54687.1; HF_1_phos.raw
53148.1; HF_2_phos.raw
53589.2; HF_3_phos.raw
54146.1; HF_4_phos.raw
52935.1; HF_5_phos.raw
Non-failing -
52941.1; NHF_1_phos.raw
52777.1; NHF_2_phos.raw
53019.2; NHF_3_phos.raw
53058.1; NHF_4_phos.raw
52621.1; NHF_5_phos.raw
2022-12-07 | MSV000090858 | MassIVE
Project description:Heart failure is a leading cause of cardiovascular mortality with limited options for treatment. We analyzed whether the anti-ischemic drug ranolazine could retard the progression of heart failure in an experimental model of heart failure induced by 6 months of chronic pressure overload. The study showed that 2 months of ranolazine treatment improved cardiac function of aortic constricted C57BL/6J (B6) mice with symptoms of heart failure as assessed by echocardiography. The microarray gene expression study of heart tissue from failing hearts relative to ranolazine-treated and healthy control hearts identified heart failure-specific genes that were normalized during treatment with the anti-ischemic drug ranolazine. Microarray gene expression profiling was performed with heart tissue isolated from three study groups: (i) untreated 10 month-old C57BL/6J (B6) mice with heart failure induced by 6 months of abdominal aortic constriction (AAC), (ii) 10 month-old B6 mice with 6 months of AAC and two months of treatment with the anti-ischemic drug ranolazine (200 mg/kg), and (iii) age-matched, untreated, sham-operated B6 control mice.
2010-12-03 | E-GEOD-25766 | biostudies-arrayexpress
Project description:The microtubule (MT) cytoskeleton can provide a mechanical resistance that can impede the motion of contracting cardiomyocytes. Yet a role of the MT network in human heart failure is unexplored. Here we utilize mass spectrometry to characterize changes to the cytoskeleton in human heart failure. Proteomic analysis of left ventricle tissue reveals a consistent upregulation and stabilization of intermediate filaments and MTs in human heart failure. This dataset includes left ventricular (LV) myocardium from 34 human hearts – either non-failing (NF) or failing hearts. NF hearts are subdivided into normal or compensated hypertrophy (cHyp), while failing hearts are subdivided into ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy with preserved or reduced ejection fraction (HCMpEF and HCMrEF, respectively). Further details on patient classification and in vivo parameters on each heart are listed in sample details.txt.
2018-06-06 | PXD008934 | Pride
Project description:Heart failure is a leading cause of cardiovascular mortality with limited options for treatment. We analyzed whether the anti-ischemic drug ranolazine could retard the progression of heart failure in an experimental model of heart failure induced by 6 months of chronic pressure overload. The study showed that 2 months of ranolazine treatment improved cardiac function of aortic constricted C57BL/6J (B6) mice with symptoms of heart failure as assessed by echocardiography. The microarray gene expression study of heart tissue from failing hearts relative to ranolazine-treated and healthy control hearts identified heart failure-specific genes that were normalized during treatment with the anti-ischemic drug ranolazine.
2010-12-03 | GSE25766 | GEO