Dataset Information

Epigenetics of Notch1 regulation in pulmonary microvascular rarefaction following extrauterine growth restriction.

ABSTRACT:

Background

Extrauterine growth restriction (EUGR) plays an important role in the developmental origin of adult cardiovascular diseases. In an EUGR rat model, we reported an elevated pulmonary arterial pressure in adults and genome-wide epigenetic modifications in pulmonary vascular endothelial cells (PVECs). However, the underlying mechanism of the early nutritional insult that results in pulmonary vascular consequences later in life remains unclear.

Methods

A rat model was used to investigate the physiological and structural effect of EUGR on early pulmonary vasculature by evaluating right ventricular systolic pressure and pulmonary vascular density in male rats. Epigenetic modifications of the Notch1 gene in PVECs were evaluated.

Results

EUGR decreased pulmonary vascular density with no significant impact on right ventricular systolic pressure at 3 weeks. Decreased transcription of Notch1 was observed both at 3 and 9 weeks, in association with decreased downstream target gene, Hes-1. Chromatin immunoprecipitation and bisulfite sequencing were performed to analyze the epigenetic modifications of the Notch1 gene promoter in PVECs. EUGR caused a significantly increased H3K27me3 in the proximal Notch1 gene promoter, and increased methylation of single CpG sites in the distal Notch1 gene promoter, both at 3 and 9 weeks.

Conclusions

We conclude that EUGR results in decreased pulmonary vascular growth in association with decreased Notch1 in PVECs. This may be mediated by increased CpG methylation and H3K27me3 in the Notch1 gene promoter region.

SUBMITTER: Tang LL

PROVIDER: S-EPMC4486133 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Publications

Epigenetics of Notch1 regulation in pulmonary microvascular rarefaction following extrauterine growth restriction.

Tang Li-Li LL Zhang Li-Yan LY Lao Lin-Jiang LJ Hu Qiong-Yao QY Gu Wei-Zhong WZ Fu Lin-Chen LC Du Li-Zhong LZ

Respiratory research 20150604

<h4>Background</h4>Extrauterine growth restriction (EUGR) plays an important role in the developmental origin of adult cardiovascular diseases. In an EUGR rat model, we reported an elevated pulmonary arterial pressure in adults and genome-wide epigenetic modifications in pulmonary vascular endothelial cells (PVECs). However, the underlying mechanism of the early nutritional insult that results in pulmonary vascular consequences later in life remains unclear.<h4>Methods</h4>A rat model was used t ...[more]

PMID: 26040933

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Project description:ObjectiveEarly postnatal life is considered as a critical time window for the determination of long-term metabolic states and organ functions. Extrauterine growth restriction (EUGR) causes the development of adult-onset chronic diseases, including pulmonary hypertension. However, the effects of nutritional disadvantages during the early postnatal period on pulmonary vascular consequences in later life are not fully understood. Our study was designed to test whether epigenetics dysregulation mediates the cellular memory of this early postnatal event.Methods and resultsTo test this hypothesis, we isolated pulmonary vascular endothelial cells by magnetic-activated cell sorting from EUGR and control rats. A postnatal insult, nutritional restriction-induced EUGR caused development of an increased pulmonary artery pressure at 9 weeks of age in male Sprague-Dawley rats. Methyl-DNA immune precipitation chip, genome-scale mapping studies to search for differentially methylated loci between control and EUGR rats, revealed significant difference in cytosine methylation between EUGR and control rats. EUGR changes the cytosine methylation at approximately 500 loci in male rats at 9 weeks of age, preceding the development of pulmonary hypertension and these represent the candidate loci for mediating the pathogenesis of pulmonary vascular disease that occurs later in life. Gene ontology analysis on differentially methylated genes showed that hypermethylated genes in EUGR are vascular development-associated genes and hypomethylated genes in EUGR are late-differentiation-associated and signal transduction genes. We validated candidate dysregulated loci with the quantitative assays of cytosine methylation and gene expressions.ConclusionThese results demonstrate that epigenetics dysregulation is a strong mechanism for propagating the cellular memory of early postnatal events, causing changes in the expression of genes and long-term susceptibility to pulmonary hypertension, and further providing a new insight into the prevention and treatment of EUGR-related pulmonary hypertension.

Project description:Early postnatal life is considered as a critical time window for determination of long-term metabolic states and organ functions. Extrauterine growth restriction (EUGR) causes the development of adult onset chronic diseases, including pulmonary arterial hypertension (PAH). However, the effects of nutritional disadvantages during early postnatal period on pulmonary vascular consequences in later life are not fully understood. Our study was designed to test whether epigentic dysregulation mediates the cellular memory of this early postnatal event. To test this hypothesis, we isolated pulmonary vascular endothelial cells (PVEC) by magnetic-activated cell sorting (MACS) from EUGR and control rats. A postnatal insult, nutritional restriction-induced EUGR caused development of an increased pulmonary artery pressure at 9-week of age in male rats. MeDIP-chip (Methyl-DNA immune precipitation chip), genome-scale mapping studies to search for differentially methylated loci between control and EUGR rats revealed significant difference in cytosine methylation between EUGR and control rats. We validated candidate dysregulated loci with quantitative assays of cytosine methylation and gene expressions. EUGR changes cytosine methylation at ~500 loci in male rats at 9 weeks of age, preceding the development of PAH and these represent candidate loci for mediating the pathogenesis of pulmonary vascular disease that occurs later in life. These results demonstrate that epigenetic dysregulation is a strong mechanism for propagating the cellular memory of early postnatal events, causing changes in expression of genes and long term susceptibility to PAH, and further providing a new insight into prevention and treatment of EUGR-related PAH. MeDIP together with microarray analysis demonstrated that significant differences in cytosine methylation between EUGR and control rats. Comparison of EUGR(n=3) vs Control (n=3) male rats' pulmonary vascular endothelial cells in 9-week age old rats

Project description:BackgroundExtrauterine growth restriction (EUGR) is common among very low birth weight (VLBW) infants and associated with poor neurodevelopmental outcomes. There are two types of EUGR definitions (cross-sectional and longitudinal) and many growth charts for monitoring postnatal growth. Aims of our study were 1) to compare the rate of small for gestational rate (SGA) and EUGR in a population of VLBW infants, both according to different growth charts (Fenton, INeS charts and Intergrowth-21) and different definitions; 2) to identify risk factors for EUGR.MethodsThis is a single centre retrospective observational study, including all VLBW infants born between January 2009 and December 2018. Anthropometric measures were obtained at birth and at discharge and presented as z-scores according to three growth charts (Fenton, INeS charts, Intergrowth-21). Maternal, clinical and nutritional data were retrieved from clinical records.Results228 VLBW were included. Percentage of SGA did not change significantly according to the three different growth charts (Fenton 22.4%, INeS charts 22.8%, Intergrowth 28.2%, p 0.27). Prevalence of EUGR was significantly higher when INeS and Fenton charts were used, compared to Intergrowth charts regardless of EUGR-definition (cross sectional-EUGR: Fenton 33.5%, INeS charts 40.9%, Intergrowth-21 23.8%, p 0.001; longitudinal-EUGR (loss of 1SDS): Fenton 15%, INeS charts 20.4%, Intergrowth 4%, p <0.001). In our population a longer time to reach 100 ml/kg/day of enteral feeding increased of 18% the risk of longitudinal EUGR. Late onset sepsis and retinopathy of prematurity were associated with an increased risk of longitudinal EUGR, although not significantly, while having a preeclamptic mother was associated with a reduced risk.ConclusionsWe confirmed a wide variability of EUGR rates when using different charts and definitions, highlighting that Intergrowth-21 charts identify less EUGR when compared to INeS and Fenton charts. Standardized criteria for defining EUGR are warranted in order to facilitate comparisons between studies and to improve the nutritional management of VLBW infants.

Project description:IntroductionPreterm birth is a leading cause of infant mortality and morbidity. Despite the improvement in the overall mortality in premature infants, the intact survival of these infants remains a significant challenge. Screening the physical growth of infants is fundamental to potentially reducing the escalation of this disorder. Recently, machine learning models have been used to predict the growth restrictions of infants; however, they frequently rely on conventional risk factors and cross-sectional data and do not leverage the longitudinal database associated with medical data from laboratory tests.MethodsThis study aimed to present an automated interpretable ML-based approach for the prediction and classification of short-term growth outcomes in preterm infants. We prepared four datasets based on weight and length including weight baseline, length baseline, weight follow-up, and length follow-up. The CHA Bundang Medical Center Neonatal Intensive Care Unit dataset was classified using two well-known supervised machine learning algorithms, namely support vector machine (SVM) and logistic regression (LR). A five-fold cross-validation, and several performance measures, including accuracy, precision, recall and F1-score were used to compare classifier performances. We further illustrated the models' trustworthiness using calibration and cumulative curves. The visualized global interpretations using Shapley additive explanation (SHAP) is provided for analyzing variables' contribution to final prediction.ResultsBased on the experimental results with area under the curve, the discrimination ability of the SVM algorithm was found to better than that of the LR model on three of the four datasets with 81%, 76% and 72% in weight follow-up, length baseline and length follow-up dataset respectively. The LR classifier achieved a better ROC score only on the weight baseline dataset with 83%. The global interpretability results revealed that pregnancy-induced hypertension, gestational age, twin birth, birth weight, antenatal corticosteroid use, premature rupture of membranes, sex, and birth length were consistently ranked as important variables in both the baseline and follow-up datasets.DiscussionThe application of machine learning models to the early detection and automated classification of short-term growth outcomes in preterm infants achieved high accuracy and may provide an efficient framework for clinical decision systems enabling more effective monitoring and facilitating timely intervention.

Dataset Information

Epigenetics of Notch1 regulation in pulmonary microvascular rarefaction following extrauterine growth restriction.

Background

Methods

Results

Conclusions

Publications

Epigenetics of Notch1 regulation in pulmonary microvascular rarefaction following extrauterine growth restriction.

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