Mitochondrial Polymerase Gamma Dysfunction and Aging Cause Cardiac Nuclear DNA Methylation Changes
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ABSTRACT:
PROVIDER: PRJNA295271 | ENA |
REPOSITORIES: ENA
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Project description:Cardiomyopathy (CM) is an intrinsic weakening of the myocardium with contractile dysfunction and congestive heart failure (CHF). CHF has been postulated to result from decreased mitochondrial energy production and oxidative stress. The effects of decreased mitochondrial oxygen consumption can also accelerate with aging, with the mitochondrial theory of aging forming the basis of this knowledge. We previously showed DNA methylation changes in human hearts with CM. This was associated with mitochondrial DNA depletion, being another molecular marker of CM. We examined the relationship between mitochondrial dysfunction and cardiac epigenetic DNA methylation changes in both young and old mice. We used genetically engineered C57Bl/6 mice transgenic for a cardiac-specific mutant of the mitochondrial polymerase (termed Y955C). Y955C mice undergo left ventricular hypertrophy (LVH) at a young age (~94 days old), and LVH decompensated to CHF at old age (~255 days old). In Y955C hearts, 95 differentially expressed genes were found, while 4,452 genes were differentially expressed in aged hearts. Moreover, cardiac DNA methylation patterns differed between Y955C (4,506 peaks with 68.5% hypomethylation) and aged hearts (73,286 peaks with 80.2% hypomethylated). Correlatively, of the 95 Y955C-dependent differentially expressed genes, 30 genes (31.6%) also displayed differential DNA methylation; in the 4,452 age dependent differentially expressed genes, 342 gene (7.7%) displayed associated DNA methylation changes. Both Y955C and aging demonstrated significant enrichment of CACGTG-associated E-box motifs in differentially methylated regions. Cardiac mitochondrial polymerase dysfunction alters nuclear DNA methylation. Furthermore, aging causes a robust change in cardiac DNA methylation that is partially associated with mitochondrial polymerase dysfunction. This study addresses how Y955C-mutated mitochondrial DNA polymerase g and aging affect cardiac (left ventricle) gene expression and epigenetic nuclear DNA methylation.
2016-05-06 | GSE72889 | GEO
Project description:Cardiomyopathy (CM) is an intrinsic weakening of the myocardium with contractile dysfunction and congestive heart failure (CHF). CHF has been postulated to result from decreased mitochondrial energy production and oxidative stress. The effects of decreased mitochondrial oxygen consumption can also accelerate with aging, with the mitochondrial theory of aging forming the basis of this knowledge. We previously showed DNA methylation changes in human hearts with CM. This was associated with mitochondrial DNA depletion, being another molecular marker of CM. We examined the relationship between mitochondrial dysfunction and cardiac epigenetic DNA methylation changes in both young and old mice. We used genetically engineered C57Bl/6 mice transgenic for a cardiac-specific mutant of the mitochondrial polymerase (termed Y955C). Y955C mice undergo left ventricular hypertrophy (LVH) at a young age (~94 days old), and LVH decompensated to CHF at old age (~255 days old). In Y955C hearts, 95 differentially expressed genes were found, while 4,452 genes were differentially expressed in aged hearts. Moreover, cardiac DNA methylation patterns differed between Y955C (4,506 peaks with 68.5% hypomethylation) and aged hearts (73,286 peaks with 80.2% hypomethylated). Correlatively, of the 95 Y955C-dependent differentially expressed genes, 30 genes (31.6%) also displayed differential DNA methylation; in the 4,452 age dependent differentially expressed genes, 342 gene (7.7%) displayed associated DNA methylation changes. Both Y955C and aging demonstrated significant enrichment of CACGTG-associated E-box motifs in differentially methylated regions. Cardiac mitochondrial polymerase dysfunction alters nuclear DNA methylation. Furthermore, aging causes a robust change in cardiac DNA methylation that is partially associated with mitochondrial polymerase dysfunction. This study addresses how Y955C-mutated mitochondrial DNA polymerase g and aging affect cardiac (left ventricle) gene expression and epigenetic nuclear DNA methylation.
2016-05-06 | GSE72888 | GEO
Project description:Cardiomyopathy (CM) is an intrinsic weakening of myocardium with contractile dysfunction and congestive heart failure (CHF). CHF has been postulated to result from decreased mitochondrial energy production and oxidative stress. Effects of decreased mitochondrial oxygen consumption also can accelerate with aging. We previously showed DNA methylation changes in human hearts with CM. This was associated with mitochondrial DNA depletion, being another molecular marker of CM. We examined the relationship between mitochondrial dysfunction and cardiac epigenetic DNA methylation changes in both young and old mice. We used genetically engineered C57Bl/6 mice transgenic for a cardiac-specific mutant of the mitochondrial polymerase-γ (termed Y955C). Y955C mice undergo left ventricular hypertrophy (LVH) at a young age (∼ 94 days old), and LVH decompensated to CHF at old age (∼ 255 days old). Results found 95 genes differentially expressed as a result of Y955C expression, while 4,452 genes were differentially expressed as a result of aging hearts. Moreover, cardiac DNA methylation patterns differed between Y955C (4,506 peaks with 68.5% hypomethylation) and aged hearts (73,286 peaks with 80.2% hypomethylated). Correlatively, of the 95 Y955C-dependent differentially expressed genes, 30 genes (31.6%) also displayed differential DNA methylation; in the 4,452 age-dependent differentially expressed genes, 342 genes (7.7%) displayed associated DNA methylation changes. Both Y955C and aging demonstrated significant enrichment of CACGTG-associated E-box motifs in differentially methylated regions. Cardiac mitochondrial polymerase dysfunction alters nuclear DNA methylation. Furthermore, aging causes a robust change in cardiac DNA methylation that is partially associated with mitochondrial polymerase dysfunction.
| S-EPMC4824151 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-05-06 | GSE72890 | GEO
Project description:Molecular signature of cardiac remodeling associated with Polymerase Gamma mutation
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Project description:Presenilin mutations that alter γ-secretase activity cause familial Alzheimer's disease (AD), whereas ApoE4, an apolipoprotein for cholesterol transport, predisposes to sporadic AD. Both sporadic and familial AD feature synaptic dysfunction. Whether γ-secretase is involved in cholesterol metabolism and whether such involvement impacts synaptic function remains unknown. Here, we show that in human neurons, chronic pharmacological or genetic suppression of γ-secretase increases synapse numbers but decreases synaptic transmission by lowering the presynaptic release probability without altering dendritic or axonal arborizations. In search of a mechanism underlying these synaptic impairments, we discovered that chronic γ-secretase suppression robustly decreases cholesterol levels in neurons but not in glia, which in turn stimulates neuron-specific cholesterol-synthesis gene expression. Suppression of cholesterol levels by HMG-CoA reductase inhibitors (statins) impaired synaptic function similar to γ-secretase inhibition. Thus, γ-secretase enables synaptic function by maintaining cholesterol levels, whereas the chronic suppression of γ-secretase impairs synapses by lowering cholesterol levels.
2023-08-06 | GSE206102 | GEO
Project description:Ancestral allele of DNA polymerase gamma modifies antiviral tolerance
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Project description:Mitochondrial Polymerase Gamma Dysfunction and Aging Cause Cardiac Nuclear DNA Methylation Changes [100718_MM9_EXP]
| PRJNA295275 | ENA
Project description:Mitochondrial Polymerase Gamma Dysfunction and Aging Cause Cardiac Nuclear DNA Methylation Changes [100929_MM9_Deluxe_Prom_Meth_HX1]
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Project description:SARS-CoV2 infection leads to cardiac injury and dysfunction in 20-30% of hospitalized patients and higher rates of mortality in patients with pre-existing cardiovascular disease. Inflammatory factors released as part of the 'cytokine storm' are thought to play a critical role in cardiac dysfunction in severe COVID-19 patients. Here we use human cardiac organoid technology combined with high sensitivity phosphoproteomics and single nuclei RNA sequencing to identify inflammatory targets inducing cardiac dysfunction. This new pipeline allowed rapid progress and identification of putative therapeutics. We identify a novel interferon-gamma driven BRD4 (bromodomain protein 4)-fibrosis/iNOS axis as a key intracellular mediator of inflammation-induced cardiac dysfunction. This axis is therapeutically targetable using BRD4 inhibitors, which promoted full recovery of function in human cardiac organoids and prevented severe inflammation and death in a cytokine-storm mouse model. The BRD inhibitor INCB054329 was the most efficacious, and is a prime candidate for drug repurposing to attenuate cardiac dysfunction and improve COVID-19 mortality in humans.
2022-02-21 | PXD020994 | Pride