Endothelial glucocorticoid receptor promoter methylation according to dexamethasone sensitivity

Mata‐Greenwood, Eugenia; Jackson, Paula; Pearce, William J.; Zhang, Li

doi:10.1530/jme-15-0124

Cited by 17 publications

(17 citation statements)

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“…Hence, differential methylation of OTX2 is a potential marker of both OCS and ICS response, and larger studies with tissue‐specific analyses are needed to confirm this association. In a prior study, differential methylation of the glucocorticoid receptor gene ( NR3C1 ) was associated with dexamethasone sensitivity in endothelial cells, but we did not find an association of NR3C1 methylation with ICS response in peripheral blood . In addition, differential methylation of genetic loci previously associated with asthma exacerbations on ICS treatment ( ST13 , FCER2 , P2RX7 , CMTR1 ) was not detected .…”

Section: Discussioncontrasting

confidence: 88%

DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics

Wang

Gruzieva

Qiu

et al. 2019

Clin Experimental Allergy

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Background Response to inhaled corticosteroids is highly variable, and the association between DNA methylation and treatment response is not known. Objective To examine the association between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma. Methods Epigenome‐wide DNA methylation was analysed in individuals on inhaled corticosteroids in three independent and ethnically diverse cohorts—Childhood Asthma Management Program (CAMP); Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE); and Genetic Epidemiology of Asthma in Costa Rica Study (GACRS). Treatment response was evaluated using two definitions, the absence of emergency department visits and/or hospitalizations and the absence oral corticosteroid use while on inhaled corticosteroid therapy. CpG sites meeting nominal significance (P < 0.05) for each outcome were combined in a three‐cohort meta‐analysis with adjustment for multiple testing. DNA methylation was correlated with gene expression using Pearson and partial correlations. Results In 154 subjects from CAMP, 72 from BAMSE, and 168 from GACRS, relative hypomethylation of cg00066816 (171 bases upstream of IL12B) was associated with the absence of emergency department visits and/or hospitalizations (Q = 0.03) in all cohorts and lower IL12B expression (ρ = 0.34, P = 0.01) in BAMSE. Relative hypermethylation of cg04256470 (688 bases upstream of CORT) was associated with the absence of oral corticosteroid use (Q = 0.04) in all cohorts and higher CORT expression (ρ = 0.20, P = 0.045) in CAMP. Conclusion and Clinical Relevance Differential DNA methylation of IL12B and CORT are associated with inhaled corticosteroid treatment response in persistent childhood asthmatics. Pharmaco‐methylation can identify novel markers of treatment sensitivity in asthma.

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Section: Discussioncontrasting

confidence: 88%

DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics

Wang

Gruzieva

Qiu

et al. 2019

Clin Experimental Allergy

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“…Although GR exon 1 6 is also broadly expressed in the rat, it only contributes about 10-20% of total GR mRNA in the adult heart [17]. Similar tissue-specific expression of GR exon 1s has been observed in the human [32]. Although exon 1B and 1C were shown to be broadly distributed in various adult tissues, expression of only exon 1C and a minor form 1G, but not exon 1B, was detected in human heart muscle [30].…”

Section: Discussionmentioning

confidence: 84%

Antenatal hypoxia induces epigenetic repression of glucocorticoid receptor and promotes ischemic-sensitive phenotype in the developing heart

Xiong

Lin

Song

et al. 2016

Journal of Molecular and Cellular Cardiology

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Large studies in humans and animals have demonstrated a clear association of an adverse intrauterine environment with an increased risk of cardiovascular disease later in life. Yet mechanisms remain largely elusive. The present study tested the hypothesis that gestational hypoxia leads to promoter hypermethylation and epigenetic repression of the glucocorticoid receptor (GR) gene in the developing heart, resulting in increased heart susceptibility to ischemia and reperfusion injury in offspring. Hypoxic treatment of pregnant rats from day 15 to 21 of gestation resulted in a significant decrease of GR exon 14, 15, 16, and 17 transcripts, leading to down-regulation of GR mRNA and protein in the fetal heart. Functional cAMP-response elements (CREs) at −4408 and −3896 and Sp1 binding sites at −3425 and −3034 were identified at GR untranslated exon 1 promoters. Hypoxia significantly increased CpG methylation at the CREs and Sp1 binding sites and decreased transcription factor binding to GR exon 1 promoter, accounting for the repression of the GR gene in the developing heart. Of importance, treatment of newborn pups with 5-aza-2’-deoxycytidine reversed hypoxia-induced promoter methylation, restored GR expression and prevented hypoxia-mediated increase in ischemia and reperfusion injury of the heart in offspring. The findings demonstrate a novel mechanism of epigenetic repression of the GR gene in fetal stress-mediated programming of ischemic-sensitive phenotype in the heart.

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“…To determine the levels of vitamin D-gene-related methylation, we performed methylated DNA immunoprecipitation (MeDIP) using a commercially available kit (Active Motif), following the manufacturer's protocol (29). Briefly, 10 g of genomic DNA was sheared four times at 30% amplitude to generate DNA fragments of 200 -500 bp.…”

Section: Methodsmentioning

confidence: 99%

Vitamin D status and metabolism in an ovine pregnancy model: effect of long-term, high-altitude hypoxia

Goyal

Billings²,

Mansour³

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Vitamin D status increases during healthy mammalian pregnancy, but the molecular determinants remain uncharacterized. The first objective of this study was to determine the effects of pregnancy, and the second objective was to examine the role of chronic hypoxia on vitamin D status and metabolism in an ovine model. We analyzed the plasma levels of cholecalciferol, 25-OH-D, and 1␣,25-(OH)2D in nonpregnant ewes, near-term pregnant ewes, and their fetuses exposed to normoxia (low altitude) or hypoxia (high-altitude) for 100 days. Hypoxic sheep had increased circulating levels of 25-OH-D and 1␣,25-(OH)2D compared with normoxic sheep. Hypoxia increases in 25-OH-D were associated with increased expression of renal 25-hydroxylases CYP2R1 and CYP2J. Pregnancy did not increase further the plasma levels of 25-OH-D, but it significantly increased those of the active metabolite, 1␣,25-(OH)2D, in both normoxic and hypoxic ewes. Increased bioactivation of vitamin D correlated with increased expression of the vitamin D-activating enzyme CYP27b1 and decreased expression of the inactivating enzyme CYP24a1 in maternal kidneys and placentas. Hypoxia increased parathyroid hormone levels and further increased renal CYP27b1. Pregnancy and hypoxia decreased the expression of vitamin D receptor (VDR) in maternal kidney and lung, with opposite effects on placental VDR. We conclude that ovine pregnancy is a model of increased vitamin D status, and long-term hypoxia further improves vitamin D status due to pregnancy-and hypoxia-specific regulation of VDR and metabolic enzymes.pregnancy; hypoxia; vitamin D; metabolism; kidney; placenta VITAMIN D HAS WELL-ESTABLISHED CLASSIC EFFECTS on bone metabolism and mineral homeostasis (8,33). In addition, vitamin D has important noncalcemic roles in the reproductive, cardiovascular, renal, lung, immune, neuronal, and pancreatic systems (8, 33). In reproduction, vitamin D deficiency has been associated with sterility, placental insufficiency, intrauterine growth restriction, recurrent miscarriages, gestational diabetes, and preeclampsia (maternal high blood pressure and proteinuria) (6, 51-53). Furthermore, maternal vitamin D deficiency has been also linked to postnatal infectious diseases, autoimmune diseases (diabetes type I), asthma, and obesity (26,28,54).Vitamin D 3 (cholecalciferol) can be produced endogenously from 7-dehydrocholesterol by sun exposure in the skin epidermis or obtained from dietary sources (8,33 (14). A classic gene regulated in this manner is the vitamin D-inactivating enzyme CYP24A1 (24-hydroxylase). Most cells that express VDR also express CYP24A1, providing a unique negative feedback control mechanism to regulate the vitamin D effects (8,14). In healthy nonpregnant mammals, the circulating levels of 1␣,25-(OH) 2 D are tightly regulated; low levels of 1␣,25-(OH) 2 D stimulate the release of parathyroid hormone (PTH) that upregulates renal CYP27b1 expression, and high levels of 1␣,25-(OH) 2 D stimulates VDR that upregulates CYP24a1 expression (8, 33).The metabolism of vitamin ...

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Endothelial glucocorticoid receptor promoter methylation according to dexamethasone sensitivity

Cited by 17 publications

References 50 publications

DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics

DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics

Antenatal hypoxia induces epigenetic repression of glucocorticoid receptor and promotes ischemic-sensitive phenotype in the developing heart

Vitamin D status and metabolism in an ovine pregnancy model: effect of long-term, high-altitude hypoxia

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