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Project description:Congenital heart disease (CHD), the leading birth defect worldwide, has a largely unknown etiology, likely to result from complex interactions between genetic and environmental factors during heart development, at a time when the heart adapts to diverse physiological and pathophysiological conditions. Crucial among these is the regulation of cardiomyocyte development and postnatal maturation, governed by dynamic changes in DNA methylation. Previous work from our laboratory has shown that exposure to the environmental toxicant tetrachlorodibenzo-p-dioxin (TCDD) disrupts several molecular networks responsible for heart development and function. To test the hypothesis that the disruption caused by TCDD in the heart results from changes in DNA methylation and gene expression patterns of cardiomyocytes, we established a stable mouse embryonic stem cell line expressing a puromycin resistance selectable marker under control of the cardiomyocyte-specific Nkx2-5 promoter. Differentiation of these cells in the presence of puromycin induces the expression of a large suite of cardiomyocyte-specific markers. To assess the consequences of TCDD treatment on gene expression and DNA methylation in these cardiomyocytes, we subjected them to transcriptome and methylome analyses in the presence of TCDD. Unlike control cardiomyocytes maintained in vehicle, the TCDD-treated cardiomyocytes showed extensive gene expression changes, with a significant correlation between differential RNA expression and DNA methylation in 111 genes, many of which are key elements of pathways that regulate cardiovascular development and function. Our findings provide an important clue toward the elucidation of the complex interactions between genetic and epigenetic mechanisms after developmental TCDD exposure that may contribute to CHD.
| S-EPMC7706406 | biostudies-literature
Project description:To test the hypothesis that the disruption caused by TCDD in cardiomyocytes results from changes in DNA methylation and gene expression patterns, we established a stable mouse embryonic stem cell line expressing a puromycin resistance selectable marker under the control of the cardiomyocyte-specific Nkx2.5 promoter. Differentiation of these cells in the presence of puromycin induces the expression of a large suite of cardiomyocyte specific markers. To assess the consequences of TCDD treatment on gene expression and DNA methylation in these cardiomyocytes, we subjected them to transcriptome and methylome analyses in the presence of TCDD. Unlike control cardiomyocytes maintained in vehicle, the TCDD-treated cardiomyocytes showed extensive gene expression changes, with a significant correlation between differential RNA expression and DNA methylation in 122 genes, many of which are key elements of pathways that regulate cardiovascular development and function. Our findings provide an important clue towards the elucidation of the complex interactions between genetic and epigenetic mechanisms, and environmental factors that may contribute to CHD incidence.
2023-07-14 | GSE154597 | GEO
Project description:To test the hypothesis that the disruption caused by TCDD in cardiomyocytes results from changes in DNA methylation and gene expression patterns, we established a stable mouse embryonic stem cell line expressing a puromycin resistance selectable marker under the control of the cardiomyocyte-specific Nkx2.5 promoter. Differentiation of these cells in the presence of puromycin induces the expression of a large suite of cardiomyocyte specific markers. To assess the consequences of TCDD treatment on gene expression and DNA methylation in these cardiomyocytes, we subjected them to transcriptome and methylome analyses in the presence of TCDD. Unlike control cardiomyocytes maintained in vehicle, the TCDD-treated cardiomyocytes showed extensive gene expression changes, with a significant correlation between differential RNA expression and DNA methylation in 122 genes, many of which are key elements of pathways that regulate cardiovascular development and function. Our findings provide an important clue towards the elucidation of the complex interactions between genetic and epigenetic mechanisms, and environmental factors that may contribute to CHD incidence.
2020-07-21 | GSE154523 | GEO
Project description:Dioxin Disrupts Dynamic DNA Methylation Patterns in Genes that Govern Cardiomyocyte Maturation
| PRJNA646751 | ENA
Project description:Dioxin Disrupts Dynamic DNA Methylation Patterns in Genes that Govern Cardiomyocyte Maturation [BiSulfite-seq]
| PRJNA646753 | ENA
Project description:Dioxin Disrupts Dynamic DNA Methylation Patterns in Genes that Govern Cardiomyocyte Maturation [RNA-seq]
| PRJNA646525 | ENA
Project description:The heart is a highly specialized organ with essential function for the organism throughout life. The significance of DNA methylation in shaping the phenotype of the heart remains only partially known. Here we generate and analyse DNA methylomes from highly purified cardiomyocytes of neonatal, adult healthy and adult failing hearts. We identify large genomic regions that are differentially methylated during cardiomyocyte development and maturation. Demethylation of cardiomyocyte gene bodies correlates strongly with increased gene expression. Silencing of demethylated genes is characterized by the polycomb mark H3K27me3 or by DNA methylation. De novo methylation by DNA methyltransferases 3A/B causes repression of fetal cardiac genes, including essential components of the cardiac sarcomere. Failing cardiomyocytes partially resemble neonatal methylation patterns. This study establishes DNA methylation as a highly dynamic process during postnatal growth of cardiomyocytes and their adaptation to pathological stress in a process tightly linked to gene regulation and activity.
| S-EPMC4220495 | biostudies-literature
Project description:Human cytochrome P450 3A (CYP3A) members are major drug-metabolizing enzymes in the liver. Two genes, CYP3A4 and CYP3A7, exhibit a developmental switch in gene expression during liver maturation. CYP3A4 is mainly expressed in adults, whereas CYP3A7 is dominantly expressed during the fetal and neonatal stages. Their ontogenic expression results in developmentally related changes in the capacity to metabolize endogenous and exogenous compounds. Thus, it is desirable to understand the mechanisms controlling the developmental switch. Mice also exhibit a developmental switch between Cyp3a16 (neonatal isoform) and Cyp3a11 (adult isoform) and may serve as a model to study the mechanisms controlling the developmental switch. Because the epigenetic code (e.g., DNA methylation and histone modifications) is implicated in regulating gene expression and cellular differentiation during development, the current study determined the status of DNA methylation, histone-3-lysine-4 dimethylation (H3K4me2) and histone-3-lysine-27 trimethylation (H3K27me3) around the mouse Cyp3a locus at various developmental ages from prenatal, through neonatal, to young adult. DNA was not hypermethylated in the Cyp3a locus at any age. However, increases in Cyp3a16 expression in neonatal livers and Cyp3a11 in adult livers were associated with increases of H3K4me2. Suppression of Cyp3a16 expression in adult livers coincided with decreases of H3K4me2 and increases of H3K27me3 around Cyp3a16. In conclusion, histone modifications of H3K4me2 and H3K27me3 are dynamically changed in a locus-specific manner along the Cyp3a locus. Developmental switch between Cyp3a11 and Cyp3a16 gene expression seems to be due to dynamic changes of histone modifications during postnatal liver maturation.
| S-EPMC2672803 | biostudies-literature
Project description:Detection of cardiomyocyte death is crucial for the diagnosis and treatment of heart disease. Here we use comparative methylome analysis to identify genomic loci that are unmethylated specifically in cardiomyocytes, and develop these as biomarkers to quantify cardiomyocyte DNA in circulating cell-free DNA (cfDNA) derived from dying cells. Plasma of healthy individuals contains essentially no cardiomyocyte cfDNA, consistent with minimal cardiac turnover. Patients with acute ST-elevation myocardial infarction show a robust cardiac cfDNA signal that correlates with levels of troponin and creatine phosphokinase (CPK), including the expected elevation-decay dynamics following coronary angioplasty. Patients with sepsis have high cardiac cfDNA concentrations that strongly predict mortality, suggesting a major role of cardiomyocyte death in mortality from sepsis. A cfDNA biomarker for cardiomyocyte death may find utility in diagnosis and monitoring of cardiac pathologies and in the study of normal human cardiac physiology and development.
| S-EPMC5915384 | biostudies-literature
Project description:BackgroundCardiomyocytes undergo major changes in DNA methylation during maturation and transition to a non-proliferative state after birth. 5'-hydroxylation of methylated cytosines (5hmC) is not only involved in DNA loss of CpG methylation but is also thought to be an epigenetic mark with unique distribution and functions. Here, we sought to get insight into the dynamics of 5'-hydroxymethylcytosine in newborn and adult cardiomyocytes.MethodsCardiomyocyte nuclei from newborn and adult C57BL/6 mice were purified by flow cytometric sorting. 5hmC-containing DNA was captured by selective chemical labeling, followed by deep sequencing. Sequencing reads of library replicates were mapped independently (n = 3 for newborn, n = 2 for adult mice) and merged for further analysis steps. 5hmC coverage was normalized to read length and the total number of mapped reads (RPKM). MethylC-Seq, ChIP-Seq and RNA-Seq data sets of newborn and adult cardiomyocytes served to elucidate specific features of 5hmC at gene bodies and around low methylated regions (LMRs) representing regulatory genomic regions with enhancer function.Results163,544 and 315,220 5hmC peaks were identified in P1 and adult cardiomyocytes, respectively. Of these peaks, 66,641 were common between P1 and adult cardiomyocytes with more than 50% reciprocal overlap. P1 and adult 5hmC peaks were overrepresented in genic features such as exons, introns, 3'- and 5'-untranslated regions (UTRs), promotors and transcription end sites (TES). During cardiomyocyte maturation, 5hmC was found to be enriched at sites of subsequent DNA loss of CpG methylation such as gene bodies of upregulated genes (i.e. Atp2a2, Tnni3, Mb, Pdk4). Additionally, centers of postnatally established enhancers were premarked by 5hmC before DNA loss of CpG methylation.ConclusionsSimultaneous analysis of 5hmC-Seq, MethylC-Seq, RNA-Seq and ChIP-Seq data at two defined time points of cardiomyocyte maturation demonstrates that 5hmC is positively associated with gene expression and decorates sites of subsequent DNA loss of CpG methylation.
| S-EPMC5112848 | biostudies-literature