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DNA methylation profiling of nenonatal murine hearts

ABSTRACT: The neonatal murine heart is able to regenerate after severe injury, however this capacity quickly diminishes within the first week of life. Since DNA methylation is one of epigenetic mechanisms that plays a crucial role in cell development and gene expression regulation, we explored the changes of DNA methylation and gene expression patterns which accompany the loss of the transient regenerative potential in the heart. We used MeDIP-chip approach in order to compare global DNA methylation profiles in the murine hearts at 1 day and 7 days after birth, as well as, in hearts of mice at the age of 2 and 8 weeks. The comparison exposed a number of DNA promoter regions significantly changing their DNA methylation status between these time-points. As the result a number of DMRs have been identified which show an overrepresentation of genes which are critical for proper heart maturation and muscle development. The methylome transition from d1 to d7 is characterized by the excess of gene regulatory regions which gain over those that lose DNA methylation, thus suggesting that a number of genes active at d1 are repressed at d7.

ORGANISM(S): Mus musculus

PROVIDER: GSE68523 | GEO | 2016/12/31

SECONDARY ACCESSION(S): PRJNA282972

REPOSITORIES: GEO

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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.

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DNA methylation profiling of nenonatal murine hearts

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