Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA412907 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6126760_1.fastq.gz | Fastqsanger.gz | |||
| SRR6126760_2.fastq.gz | Fastqsanger.gz | |||
| SRR6126761_1.fastq.gz | Fastqsanger.gz | |||
| SRR6126761_2.fastq.gz | Fastqsanger.gz | |||
| SRR6126756_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Maternal hyperglycemia increases the risk of CHD and is further sensitized by haploinsufficiency of Notch1 supporting a gene-environment interaction model. To gain insights into chromatin accessible status by which hyperglycemia affects molecular pathways regulating cardiac development, we performed ATAC-seq on embryonic AV cushion mesenchymal cells maintained in normal and high glucose.
2017-10-03 | GSE104520 | GEO
Project description:Birth defects are the leading cause of infant mortality, and they are caused by a combination of genetic and environmental factors. Environmental risk factors may contribute to birth defects in genetically susceptible infants by altering critical molecular pathways during embryogenesis, but experimental evidence for gene-environment interactions is limited. Fetal hyperglycemia associated with maternal diabetes results in a 5-fold increased risk of congenital heart disease (CHD), but the molecular basis for this correlation is unknown. Here, we show that the effects of maternal hyperglycemia on cardiac development are sensitized by haploinsufficiency of Notch1, a key transcriptional regulator known to cause CHD. Using ATAC-seq, we found that hyperglycemia decreased chromatin accessibility at the endothelial NO synthase (Nos3) locus, resulting in reduced NO synthesis. Transcription of Jarid2, a regulator of histone methyltransferase complexes, was increased in response to reduced NO, and this upregulation directly resulted in inhibition of Notch1 expression to levels below a threshold necessary for normal heart development. We extended these findings using a Drosophila maternal diabetic model that revealed the evolutionary conservation of this interaction and the Jarid2-mediated mechanism. These findings identify a gene-environment interaction between maternal hyperglycemia and Notch signaling and support a model in which environmental factors cause birth defects in genetically susceptible infants.
| S-EPMC5846898 | biostudies-other
Project description:Congenital heart disease (CHD) is the most prevalent structural malformations of the heart affecting ∼1% of live births. To date, both damaging genetic variations and adverse environmental exposure such as maternal diabetes have been found to cause CHD. Clinical studies show ∼fivefold higher risk of CHD in the offspring of mothers with pregestational diabetes. Maternal pregestational diabetes affects the gene regulatory networks key to proper cardiac development in the fetus. However, the cell-type specificity of these gene regulatory responses to maternal diabetes and their association with the observed cardiac defects in the fetuses remains unknown. To uncover the transcriptional responses to maternal diabetes in the early embryonic heart, we used an established murine model of pregestational diabetes. In this model, we have previously demonstrated an increased incidence of CHD. Here, we show maternal hyperglycemia (matHG) elicits diverse cellular responses during heart development by single-cell RNA-sequencing in embryonic hearts exposed to control and matHG environment. Through differential gene-expression and pseudotime trajectory analyses of this data, we identified changes in lineage specifying transcription factors, predominantly affecting Isl1+ second heart field progenitors and Tnnt2+cardiomyocytes with matHG. Using in vivo cell-lineage tracing studies, we confirmed that matHG exposure leads to impaired second heart field-derived cardiomyocyte differentiation. Finally, this work identifies matHG-mediated transcriptional determinants in cardiac cell lineages elevate CHD risk and show perturbations in Isl1-dependent gene-regulatory network (Isl1-GRN) affect cardiomyocyte differentiation. Functional analysis of this GRN in cardiac progenitor cells will provide further mechanistic insights into matHG-induced severity of CHD associated with diabetic pregnancies.
2022-07-22 | GSE193746 | GEO
Project description:The prevalence of diabetes has significantly increased among women of childbearing age worldwide, and it is known that infants who are exposed to maternal diabetes in utero are at increased risk of congenital anomalies of the kidney and urinary tract. The primary role of the kidney is to filter blood through the nephrons. These anomalies can result in a reduction in the number of nephrons that are formed during kidney development, or decreased congenital nephron endowment, which is linked to hypertension and chronic kidney disease. It is unknown how exposure to maternal diabetes in utero results in abnormal kidney development and the long-term health consequences of this exposure remain ill-defined. In this study, we profiled gene expression in the developing mouse kidney from C57BL/6J control and maternal diabetes exposed (DM_Exp) mice at single cell resolution. Consistent with previous studies, clusters with distinct transcriptional signatures clearly identify major compartments and cell types of the developing kidney.
2024-11-01 | GSE162298 | GEO
Project description:Maternal diabetes is a recognized risk factor for both short-term and long-term complications in offspring. Beyond the direct teratogenicity of maternal diabetes, the intrauterine environment can influence offspring cardiovascular health. Abnormalities in the cardiac sympathetic system are implicated in conditions such as sudden infant death syndrome, cardiac arrhythmic death, heart failure, and certain congenital heart defects in children from diabetic pregnancies. However, the mechanisms by which maternal diabetes affect the development of the cardiac sympathetic system and consequently, heightening health risks and predisposing to cardiovascular disease remain poorly understood. In this study, we present a comprehensive analysis of the combined impact of a Hif1a-deficient sympathetic system and the maternal diabetes environment on both heart development and the formation of the cardiac sympathetic system. The synergic negative effect of exposure to maternal diabetes and Hif1a deficiency resulted in the most pronounced deficit in cardiac sympathetic innervation and the development of adrenal medulla. Abnormalities in the cardiac sympathetic system were accompanied by a smaller heart, reduced ventricular wall thickness, dilated subepicardial veins, and coronary arteries in the myocardium, along with anomalies in the branching and connections of the main coronary arteries. Transcriptional profiling by RNA-seq revealed significant transcriptome changes in Hif1a-deficient sympathetic neurons, primarily associated with cell cycle regulation, proliferation, and mitosis, explaining the shrinkage of the sympathetic neuron population. Our data demonstrate that a failure to adequately activate HIF-1α regulatory pathway, particularly in the context of maternal diabetes, may contribute to abnormalities in the cardiac sympathetic system. In conclusion, our findings indicate that the interplay between deficiencies in the cardiac sympathetic system and subtle structural alternations in the vasculature, microvasculature, and myocardium during heart development not only increases the risk of cardiovascular disease but also diminishes the adaptability to the stress associated with the transition to extrauterine life, thus, increasing the risk of neonatal death.
2024-02-29 | GSE250606 | GEO
Project description:Human iPSC-derived organoids modeling the etiology of pregestational diabetes induced congenital heart defects
2023-08-07 | GSE201343 | GEO
Project description:We analysed the combined effects of exposure to maternal diabetes and disrupted HIF-1 signaling on the transcriptom in cardiac left ventricles of 12 weeks old male mice. This approach provides the information about the long term changes originating in utero due to maternal diabetes and inefficient response to hypoxia which develops as a result of hyperglycemia. The majority of changes were detected in Hif1a insufficient mice exposed to maternal diabetes.
2018-05-15 | GSE109633 | GEO
Project description:Diabetic embryopathy can affect any developing organ system, although cardiovascular malformations, neural tube defects and caudal dysgenesis syndrome are the most prominent congenital malformations. We hypothesize that the metabolic imbalance occurring in diabetic pregnancy de-regulates tissue specific gene expression programs in the developing embryo. In order to identify genes whose expression is affected by maternal diabetes, we analyzed gene expression profiles of diabetes-exposed mouse embryos by using Affymetrix microarrays. We identified 129 genes with altered expression levels; 21 genes had increased and 108 genes had decreased expression levels in diabetes-exposed embryos relative to controls. A substantial fraction of these genes (35) are essential for normal embryonic development as shown by functional studies in mouse models. The largest fraction of diabetes-affected genes was in transcription factor and DNA-binding/chromatin remodeling functional categories (19%), which directly affect transcription. These findings suggest that transcriptional regulation in the developing embryos is perturbed by maternal diabetes and that transcriptional regulation plays a major role in the responses of embryos to intrauterine exposure to diabetic conditions. Interestingly, we found the expression of hypoxia-inducible factor 1 α (Hif1α) deregulated in the embryos exposed to the conditions of maternal diabetes. Since hypoxic stress is associated with the complications of diabetic pregnancy, we performed a post-hoc analysis of our microarray data with a specific focus on known HIF1 target genes. Of 39 genes detected in our microarrays, the expression changes of 22 genes (20 were increased and two genes were decreased in diabetes-exposed embryos) were statistically significant. These results indicate that HIF1-regulated pathways are affected in diabetes-exposed embryos. These results strongly suggest that de-regulation of hypoxia/HIF1 activated pathways could be the one of the key molecular events associated with the exposure to the teratogenic intrauterine environment of a diabetic mother. Keywords: Comparative studies of embryonic response to maternal diabetes
2009-07-21 | GSE9675 | GEO
Project description:Congenital heart disease associated bronchopulmonary dysplasia and its underlying mechanisms
| PRJNA832120 | ENA
Project description:Congenital heart disease (CHD) is the most frequent birth defect and affects nearly 1% of newborns. The etiology of CHD is largely unknown and only a small percentage can be assigned to environmental risk factors such as maternal diseases or exposure to mutagenic agents during pregnancy. Chromosomal imbalances have been identified in many forms of syndromic CHD, but next to nothing is known about the impact of DNA copy number changes in non-syndromic CHD. Here we present a sub-megabase resolution array CGH screen of a cohort with CHD as the sole abnormality at the time of diagnosis. Keywords: array CGH In this BAC array CGH study 104 patients with congenital heart disease and some of their parents were screened for DNA copy number changes at submegabase resolution. No dye swap was performed.
2008-05-11 | E-GEOD-7527 | biostudies-arrayexpress