scholarly journals Glucocorticoid Programming of the Fetal Male Hippocampal Epigenome

Endocrinology ◽  
2013 ◽  
Vol 154 (3) ◽  
pp. 1168-1180 ◽  
Author(s):  
Ariann Crudo ◽  
Matthew Suderman ◽  
Vasilis G. Moisiadis ◽  
Sophie Petropoulos ◽  
Alisa Kostaki ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Promoter Methylation ◽  
Plasma Cortisol ◽  
Late Gestation ◽  
Gene Promoters ◽  
Fetal Plasma ◽  
Genome Wide ◽  
Organ Systems ◽  
Increased Risk ◽  
H3k9 Acetylation

Abstract The late-gestation surge in fetal plasma cortisol is critical for maturation of fetal organ systems. As a result, synthetic glucocorticoids (sGCs) are administered to pregnant women at risk of delivering preterm. However, animal studies have shown that fetal exposure to sGC results in increased risk of behavioral, endocrine, and metabolic abnormalities in offspring. Here, we test the hypothesis that prenatal GC exposure resulting from the fetal cortisol surge or after sGC exposure results in promoter-specific epigenetic changes in the hippocampus. Fetal guinea pig hippocampi were collected before (gestational day [GD52]) and after (GD65) the fetal plasma cortisol surge (Term∼GD67) and 24 hours after (GD52) and 14 days after (GD65) two repeat courses of maternal sGC (betamethasone) treatment (n = 3–4/gp). We identified extensive genome-wide alterations in promoter methylation in late fetal development (coincident with the fetal cortisol surge), whereby the majority of the affected promoters exhibited hypomethylation. Fetuses exposed to sGC in late gestation exhibited substantial differences in DNA methylation and histone h3 lysine 9 (H3K9) acetylation in specific gene promoters; 24 hours after the sGC treatment, the majority of genes affected were hypomethylated or hyperacetylated. However, 14 days after sGC exposure these differences did not persist, whereas other promoters became hypermethylated or hyperacetylated. These data support the hypothesis that the fetal GC surge is responsible, in part, for significant variations in genome-wide promoter methylation and that prenatal sGC treatment profoundly changes the epigenetic landscape, affecting both DNA methylation and H3K9 acetylation. This is important given the widespread use of sGC in the management of women in preterm labor.

scholarly journals Prenatal Synthetic Glucocorticoid Treatment Changes DNA Methylation States in Male Organ Systems: Multigenerational Effects

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3269-3283 ◽  
Author(s):  
Ariann Crudo ◽  
Sophie Petropoulos ◽  
Vasilis G. Moisiadis ◽  
Majid Iqbal ◽  
Alisa Kostaki ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Critical Role ◽  
Covalent Modification ◽  
Late Gestation ◽  
Next Generation ◽  
Long Term Effects ◽  
Glucocorticoid Treatment ◽  
Epigenetic State ◽  
Organ Systems ◽  
Increased Risk

Prenatal synthetic glucocorticoids (sGC) are administered to pregnant women at risk of delivering preterm, approximately 10% of all pregnancies. Animal studies have demonstrated that offspring exposed to elevated glucocorticoids, either by administration of sGC or as a result of maternal stress, are at increased risk of developing behavioral, endocrine, and metabolic abnormalities. DNA methylation is a covalent modification of DNA that plays a critical role in long-lasting programming of gene expression. Here we tested the hypothesis that prenatal sGC treatment has both acute and long-term effects on DNA methylation states in the fetus and offspring and that these effects extend into a subsequent generation. Pregnant guinea pigs were treated with sGC in late gestation, and methylation analysis by luminometric methylation assay was undertaken in organs from fetuses and offspring across two generations. Expression of genes that modify the epigenetic state were measured by quantitative real-time PCR. Results indicate that there are organ-specific developmental trajectories of methylation in the fetus and newborn. Furthermore, these trajectories are substantially modified by intrauterine exposure to sGC. These sGC-induced changes in DNA methylation remain into adulthood and are evident in the next generation. Furthermore, prenatal sGC exposure alters the expression of several genes encoding proteins that modulate the epigenetic state. Several of these changes are long lasting and are also present in the next generation. These data support the hypothesis that prenatal sGC exposure leads to broad changes in critical components of the epigenetic machinery and that these effects can pass to the next generation.

scholarly journals Effects of Antenatal Synthetic Glucocorticoid on Glucocorticoid Receptor Binding, DNA Methylation, and Genome-Wide mRNA Levels in the Fetal Male Hippocampus

Endocrinology ◽  
2013 ◽  
Vol 154 (11) ◽  
pp. 4170-4181 ◽  
Author(s):  
Ariann Crudo ◽  
Sophie Petropoulos ◽  
Matthew Suderman ◽  
Vasilis G. Moisiadis ◽  
Alisa Kostaki ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Fetal Lung ◽  
Late Gestation ◽  
Mrna Levels ◽  
Substantial Impact ◽  
Genome Wide ◽  
Organ Systems ◽  
Endogenous Cortisol

The endogenous glucocorticoid (GC) surge in late gestation plays a vital role in maturation of several organ systems. For this reason, pregnant women at risk of preterm labor are administered synthetic glucocorticoids (sGCs) to promote fetal lung development. Animal studies have shown that fetal sGC exposure can cause life-long changes in endocrine and metabolic function. We have previously shown that antenatal sGC treatment is associated with alterations in global DNA methylation and modifications to the hippocampal methylome and acetylome. In this study, we hypothesized that: 1) there are changes in the transcriptional landscape of the fetal hippocampus in late gestation, associated with the endogenous cortisol surge; 2) fetal sGC exposure alters genome-wide transcription in the hippocampus; and 3) these changes in transcription are associated with modified glucocorticoid receptor (GR) DNA binding and DNA methylation. sGC was administered as 2 courses on gestational days (GD) 40, 41, 50, and 51, and the hippocampi of fetal guinea pigs were examined before (GD52) and after (GD65) the endogenous cortisol surge (Term ∼GD67). We also analyzed fetal hippocampi 24 hours and 14 days following maternal sGC injections (n = 3–4/group). Genome-wide modification of transcription and GR DNA binding occurred in late gestation, in parallel with the normal GC surge. Further, sGC exposure had a substantial impact on the hippocampal transcriptome, GR-DNA binding, and DNA methylation at 24 hours and 14 days following the final sGC treatment. These data support the hypothesis that GC exposure in late gestation plays a significant role in modifying the transcriptional and epigenetic landscape of the developing fetal hippocampus and that substantial effects are evident for at least 2 weeks after sGC exposure.

Abstract 40: Disturbed Flow Alters Genomewide DNA Methylation Patterns, Regulating Endothelial Gene Expression and Atherosclerosis

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Jessilyn Dunn ◽  
Haiwei Qiu ◽  
Soyeon Kim ◽  
Daudi Jjingo ◽  
Ryan Hoffman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Western Diet ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Genome Wide ◽  
Methylation Patterns ◽  
Endothelial Gene Expression

Atherosclerosis preferentially occurs in arterial regions of disturbed blood flow (d-flow), which alters gene expression, endothelial function, and atherosclerosis. Here, we show that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase (DNMT)-dependent manner. We found that d-flow induced expression of DNMT1, but not DNMT3a or DNMT3b, in mouse arterial endothelium in vivo and in cultured endothelial cells by oscillatory shear (OS) compared to unidirectional laminar shear in vitro. The DNMT inhibitor 5-Aza-2’deoxycytidine (5Aza) or DNMT1 siRNA significantly reduced OS-induced endothelial inflammation. Moreover, 5Aza reduced lesion formation in two atherosclerosis models using ApoE-/- mice (western diet for 3 months and the partial carotid ligation model with western diet for 3 weeks). To identify the 5Aza mechanisms, we conducted two genome-wide studies: reduced representation bisulfite sequencing (RRBS) and transcript microarray using endothelial-enriched gDNA and RNA, respectively, obtained from the partially-ligated left common carotid artery (LCA exposed to d-flow) and the right contralateral control (RCA exposed to s-flow) of mice treated with 5Aza or vehicle. D-flow induced DNA hypermethylation in 421 gene promoters, which was significantly prevented by 5Aza in 335 genes. Systems biological analyses using the RRBS and the transcriptome data revealed 11 mechanosensitive genes whose promoters were hypermethylated by d-flow but rescued by 5Aza treatment. Of those, five genes contain hypermethylated cAMP-response-elements in their promoters, including the transcription factors HoxA5 and Klf3. Their methylation status could serve as a mechanosensitive master switch in endothelial gene expression. Our results demonstrate that d-flow controls epigenomic DNA methylation patterns in a DNMT-dependent manner, which in turn alters endothelial gene expression and induces atherosclerosis.

scholarly journals DNA methylation marks inter-nucleosome linker regions throughout the human genome

2013 ◽  
Author(s):  
Benjamin P. Berman ◽  
Yaping Liu ◽  
Theresa K. Kelly
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
Cpg Dinucleotides ◽  
Sequencing Technologies ◽  
Nucleosome Organization ◽  
Genome Wide ◽  
A Genome ◽  
Sequencing Studies

Background: Nucleosome organization and DNA methylation are two mechanisms that are important for proper control of mammalian transcription, as well as epigenetic dysregulation associated with cancer. Whole-genome DNA methylation sequencing studies have found that methylation levels in the human genome show periodicities of approximately 190 bp, suggesting a genome-wide relationship between the two marks. A recent report (Chodavarapu et al., 2010) attributed this to higher methylation levels of DNA within nucleosomes. Here, we analyzed a number of published datasets and found a more compelling alternative explanation, namely that methylation levels are highest in linker regions between nucleosomes. Results: Reanalyzing the data from (Chodavarapu et al., 2010), we found that nucleosome-associated methylation could be strongly confounded by known sequence-related biases of the next-generation sequencing technologies. By accounting for these biases and using an unrelated nucleosome profiling technology, NOMe-seq, we found that genome-wide methylation was actually highest within linker regions occurring between nucleosomes in multi-nucleosome arrays. This effect was consistent among several methylation datasets generated independently using two unrelated methylation assays. Linker-associated methylation was most prominent within long Partially Methylated Domains (PMDs) and the positioned nucleosomes that flank CTCF binding sites. CTCF adjacent nucleosomes retained the correct positioning in regions completely devoid of CpG dinucleotides, suggesting that DNA methylation is not required for proper nucleosomes positioning. Conclusions: The biological mechanisms responsible for DNA methylation patterns outside of gene promoters remain poorly understood. We identified a significant genome-wide relationship between nucleosome organization and DNA methylation, which can be used to more accurately analyze and understand the epigenetic changes that accompany cancer and other diseases.

scholarly journals Bacterial Lipopolysaccharide Induced Alterations of Genome-Wide DNA Methylation and Promoter Methylation of Lactation-Related Genes in Bovine Mammary Epithelial Cells

Toxins ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 298 ◽  
Author(s):  
Jingbo Chen ◽  
Yongjiang Wu ◽  
Yawang Sun ◽  
Xianwen Dong ◽  
Zili Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Response ◽  
Mrna Expression ◽  
Promoter Methylation ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Bovine Mammary Epithelial Cells ◽  
Genome Wide ◽  
Immune Response Pathway ◽  
Gene Mrna

Bacterial lipopolysaccharide (LPS) could result in poor lactation performance in dairy cows. High methylation of DNA is associated with gene repression. However, it is unclear whether LPS could suppress the expression of lactation-related genes by inducing DNA methylation. Therefore, the objective of this study was to investigate the impact of LPS on genome-wide DNA methylation, using methylated DNA immunoprecipitation with high-throughput sequencing (MeDIP-seq) and on the promoter methylation of lactation-related genes using MassArray analysis in bovine mammary epithelial cells. The bovine mammary epithelial cell line MAC-T cells were treated for 48 h with LPS at different doses of 0, 1, 10, 100, and 1000 endotoxin units (EU)/mL (1 EU = 0.1 ng). The results showed that the genomic methylation levels and the number of methylated genes in the genome as well as the promoter methylation levels of milk genes increased when the LPS dose was raised from 0 to 10 EU/mL, but decreased after further increasing the LPS dose. The milk gene mRNA expression levels of the 10 EU/mL LPS treatment were significantly lower than these of untreated cells. The results also showed that the number of hypermethylated genes was greater than that of hypomethylated genes in lipid and amino acid metabolic pathways following 1 and 10 EU/mL LPS treatments as compared with control. By contrast, in the immune response pathway the number of hypomethylated genes increased with increasing LPS doses. The results indicate LPS at lower doses induced hypermethylation of the genome and promoters of lactation-related genes, affecting milk gene mRNA expression. However, LPS at higher doses induced hypomethylation of genes involved in the immune response pathway probably in favor of immune responses.

Genome-wide screening identifies Plasmodium chabaudi-induced modifications of DNA methylation status of Tlr1 and Tlr6 gene promoters in liver, but not spleen, of female C57BL/6 mice

2013 ◽  
Vol 112 (11) ◽  
pp. 3757-3770 ◽  
Author(s):  
Saleh Al-Quraishy ◽  
Mohamed A. Dkhil ◽  
Abdel Azeem S. Abdel-Baki ◽  
Denis Delic ◽  
Simeon Santourlidis ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Methylation Status ◽  
Gene Promoters ◽  
Plasmodium Chabaudi ◽  
Genome Wide

scholarly journals Genome-wide DNA methylation can identify preterm birth-related genes in maternal blood

2020 ◽  
Author(s):  
Young-Ah You ◽  
Eun Jin Kwon ◽  
Han-Sung Hwang ◽  
Suk-Joo Choi ◽  
Sae Kyung Choi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Preterm Birth ◽  
Maternal Blood ◽  
Differential Methylation ◽  
Multiple Tests ◽  
Cpg Sites ◽  
Genome Wide ◽  
Increased Risk ◽  
Health And Disease ◽  
Whole Blood Cells

Abstract Background Preterm birth is associated with an increased risk of neonatal complications and death, as well as poor health and disease later in life. Epigenetics could contribute to the mechanism underlying preterm birth. Results Genome-wide DNA methylation in whole blood cells from ten women was assessed using Illumina Infinium HumanMethylation450 BeadChips array. We identified 6,755 differentially methylated CpG sites between term and preterm birth. Although no differential methylation of these CpGs were found in correcting for multiple tests, seven VTRNA2-1 CpGs in promotor region of island were detected in top different methylation. We performed pyrosequencing validation with blood samples from the pregnant women. The methylation levels of VTRNA2-1 were either low (hypomethylated, 0–12.2%) or high (hypermethylated, 32.6–50.8%). Hypermethylation of VTRNA2-1 was associated with an increased risk of preterm birth after adjusting for maternal age, delivered season, parity and count of white blood cell. The mRNA expression of VTRNA2-1 was 0.51-fold lower in PTB delivered women compared with women with term deliveries. Conclusion This study suggests that change of VTRNA2-1 methylation is related to PTB in maternal blood. Further elucidate to underlay mechanisms of preterm birth and affect to future systems biology studies to predict preterm birth.

scholarly journals DNA methylation marks inter-nucleosome linker regions throughout the human genome

2013 ◽  
Author(s):  
Benjamin P. Berman ◽  
Yaping Liu ◽  
Theresa K. Kelly
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
Cpg Dinucleotides ◽  
Sequencing Technologies ◽  
Nucleosome Organization ◽  
Genome Wide ◽  
A Genome ◽  
Sequencing Studies

Background: Nucleosome organization and DNA methylation are two mechanisms that are important for proper control of mammalian transcription, as well as epigenetic dysregulation associated with cancer. Whole-genome DNA methylation sequencing studies have found that methylation levels in the human genome show periodicities of approximately 190 bp, suggesting a genome-wide relationship between the two marks. A recent report (Chodavarapu et al., 2010) attributed this to higher methylation levels of DNA within nucleosomes. Here, we analyzed a number of published datasets and found a more compelling alternative explanation, namely that methylation levels are highest in linker regions between nucleosomes. Results: Reanalyzing the data from (Chodavarapu et al., 2010), we found that nucleosome-associated methylation could be strongly confounded by known sequence-related biases of the next-generation sequencing technologies. By accounting for these biases and using an unrelated nucleosome profiling technology, NOMe-seq, we found that genome-wide methylation was actually highest within linker regions occurring between nucleosomes in multi-nucleosome arrays. This effect was consistent among several methylation datasets generated independently using two unrelated methylation assays. Linker-associated methylation was most prominent within long Partially Methylated Domains (PMDs) and the positioned nucleosomes that flank CTCF binding sites. CTCF adjacent nucleosomes retained the correct positioning in regions completely devoid of CpG dinucleotides, suggesting that DNA methylation is not required for proper nucleosomes positioning. Conclusions: The biological mechanisms responsible for DNA methylation patterns outside of gene promoters remain poorly understood. We identified a significant genome-wide relationship between nucleosome organization and DNA methylation, which can be used to more accurately analyze and understand the epigenetic changes that accompany cancer and other diseases.

Blood pressure and heart rate in the ovine fetus: ontogenic changes and effects of fetal adrenalectomy

1999 ◽  
Vol 276 (1) ◽  
pp. H248-H256 ◽  
Author(s):  
Nobuya Unno ◽  
Chi H. Wong ◽  
Susan L. Jenkins ◽  
Richard A. Wentworth ◽  
Xiu-Ying Ding ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Plasma Cortisol ◽  
Time Windows ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Long Term Study ◽  
Arterial Blood ◽  
Ovine Fetus

Ontogenic changes in baseline and 24-h rhythms of fetal arterial blood pressure (FABP) and heart rate (FHR) and their regulation by the fetal adrenal were studied in 18 fetal sheep chronically instrumented at 109–114 days gestation (GA). In the long-term study, FABP and FHR were continuously recorded from 120 days GA to spontaneous term labor (>145 days GA) in five animals. Peak times (PT) and amplitudes (Amp) of cosinor analysis were compared at 120–126, 127–133, and 134–140 days GA. Consistent, significant linear increases in FABP and linear decreases in FHR were observed in all fetuses. Significant 24-h rhythms in FABP and FHR were observed during all the time windows. In the adrenalectomy study, to test the hypothesis that fetal cortisol plays a key role in cardiovascular maturation, fetal adrenals were removed in eight animals (ADX); sham fetal adrenalectomy was performed on five animals (Con). Cortisol (4 μg/min) was infused intravenously in four ADX fetuses from day 7postsurgery for 7 days (ADX+F). No significant changes in PT and Amp in FABP and FHR were observed. Plasma cortisol levels remained low in Con and ADX fetuses (<4.9 ng/ml). Cortisol infusion increased fetal plasma cortisol to 22.3 ± 3.2 ng/ml (mean ± SE) on day 13 in ADX+F fetuses. FABP increased in control and ADX+F but not ADX fetuses; FHR decreased in control and ADX but rose in ADX+F fetuses. These results suggest that, in chronically instrumented fetal sheep at late gestation, 1) increases in FABP and decreases in FHR are maintained consistently from 120 to 140 days GA, with distinct 24-h rhythms, the PT and Amp of which remain unchanged, and 2) the physiological increase in FABP is dependent on the fetal adrenal; bilateral removal of the fetal adrenals does not prevent the ability of cortisol to produce a sustained increase in FABP.

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