Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA275258 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1800178.fastq.gz | Fastqsanger.gz | |||
| SRR1800179.fastq.gz | Fastqsanger.gz |
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Project description:Cardiac metabolism is deranged in heart failure, but underlying mechanisms remain unclear. Lysine demethylase 8 (Kdm8) represses gene expression in the embryo and controls metabolism in cancer. However, its function in cardiac homeostasis is unknown. We show that Kdm8 maintains a mitochondrial gene network active by repressing Tbx15 to prevent dilated cardiomyopathy leading to lethal heart failure. Deletion of Kdm8 in mouse cardiomyocytes increased H3K36me2 with activation of Tbx15 and repression of target genes in the NAD+ pathway before dilated cardiomyopathy initiates. Moreover, NAD+ supplementation prevented dilated cardiomyopathy in Kdm8 mutant mice and TBX15 overexpression blunted NAD+-activated cardiomyocyte respiration. Furthermore, KDM8 was downregulated in human hearts affected by dilated cardiomyopathy and higher TBX15 expression defines a subgroup of affected hearts with the strongest downregulation of genes encoding mitochondrial proteins. Thus, KDM8 represses TBX15 to maintain cardiac metabolism. Our results suggest that epigenetic dysregulation of metabolic gene networks initiates myocardium deterioration towards heart failure and could underlie heterogeneity of dilated cardiomyopathy.
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Project description:Importantly, mutations in nuclear envelope-encoding genes are the second-highest cause of familial dilated cardiomyopathy. One such nuclear envelope protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in mechanically active tissue such as heart remains poorly understood.
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Project description:Cardiac metabolism is deranged in heart failure, but underlying mechanisms remain unclear. Lysine demethylase 8 (Kdm8) represses gene expression in the embryo and controls metabolism in cancer. However, its function in cardiac homeostasis is unknown. We show that Kdm8 maintains a mitochondrial gene network active by repressing Tbx15 to prevent dilated cardiomyopathy leading to lethal heart failure. Deletion of Kdm8 in mouse cardiomyocytes increased H3K36me2 with activation of Tbx15 and repression of target genes in the NAD+ pathway before dilated cardiomyopathy initiates. Moreover, NAD+ supplementation prevented dilated cardiomyopathy in Kdm8 mutant mice and TBX15 overexpression blunted NAD+-activated cardiomyocyte respiration. Furthermore, KDM8 was downregulated in human hearts affected by dilated cardiomyopathy and higher TBX15 expression defines a subgroup of affected hearts with the strongest downregulation of genes encoding mitochondrial proteins. Thus, KDM8 represses TBX15 to maintain cardiac metabolism. Our results suggest that epigenetic dysregulation of metabolic gene networks initiates myocardium deterioration towards heart failure and could underlie heterogeneity of dilated cardiomyopathy.
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Project description:Loss of the Melanocortin 4 Receptor in mice causes dilated cardiomyopathy.
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Project description:A novel ppp1r13l sequence variation causes dilated cardiomyopathy and cardiac inflammation. This experiment explores the transcriptome of wa3 mice hearts which are carry deletion and insertion mutations in exon 12 of the Ppp1r13l gene that generate premature stop codon, and exhibit dilated cardio myopathy in a similar manner to a novel human mutation that was recently dicovered.
2017-06-13 | E-MTAB-5812 | biostudies-arrayexpress
Project description:<p>BACKGROUND: Imbalances in cardiac branched-chain amino acid (BCAA) metabolism and mitochondrial homeostasis are implicated in the onset and development of heart failure. However, the mechanisms triggering the downregulation of cardiac BCAA metabolism in heart failure remain unclear. Here, we identify a novel role of RNA-binding protein GRSF1 (guanine-rich RNA sequence binding factor 1) in post-transcriptionally regulating cell-intrinsic BCAA metabolic pathways, ultimately contributing to the pathogenesis of heart failure.</p><p>METHODS: We examined GRSF1 expression in the heart tissues of patients with dilated cardiomyopathy and generated mice with cardiomyocyte-specific deletion or overexpression of GRSF1 in vivo to investigate its role in heart failure. The effect of GRSF1 on BCAA homeostasis was assessed through untargeted and targeted metabolomics and mitochondrial function analysis. To elucidate the mechanisms underlying GRSF1-mediated metabolic regulation, we employed mice with cardiomyocyte-specific deletion of BCKDHB, and mice with cardiomyocyte-specific expression of GRSF1 lacking a quasi-RNA recognition motif. </p><p>RESULTS: GRSF1 expression was significantly decreased in the hearts of patients with heart failure and failing murine hearts. Cardiomyocyte-specific GRSF1 deletion resulted in cardiac dysfunction, spontaneous progression to dilated cardiomyopathy, and heart failure, accompanied by increased cardiac hypertrophy and fibrosis. Conversely, GRSF1 overexpression attenuated cardiac remodeling and heart failure induced by transverse aortic constriction. Mechanistically, GRSF1 maintained BCAA homeostasis and mitochondrial function by directly interacting with the G-tracts in coding region of BCKDHB mRNA through a quasi-RNA recognition motif to promote the stability of BCKDHB mRNA at the post-transcriptional level, thereby increasing its protein expression. Functional recovery mediated by GRSF1 overexpression in cardiomyocytes was partially blocked upon cardiac-specific deletion of BCKDHB. </p><p>CONCLUSIONS: Our study identified GRSF1 as a cell-intrinsic metabolic checkpoint that maintains cardiac BCAA homeostasis by regulating BCKDHB mRNA turnover. Targeting GRSF1 may offer therapeutic benefits for heart failure and other cardiometabolic diseases requiring BCAA manipulation.</p>
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Project description:Loss of Cardiac microRNA-Mediated Regulation Leads to Dilated Cardiomyopathy and Heart Failure.
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Project description:Characterization of plasma metabolomic profile of 15 patients with advanced heart failure referred for heart transplantation (8 patients with chronic chagasic cardiomyopathy and 7 with idiopathic dilated cardiomyopathy) and 12 heart donor individuals using gas chromatography/quadrupole time-of-flight mass spectrometry.
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