scholarly journals Supplementation of Choline-Deficient Diet With Pterostilbene Attenuates Cancer Development and Epigenetic Dysregulation of Gene Expression in Rat Livers

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 280-280
Author(s):  
Barbara Stefanska ◽  
Cayla Boycott ◽  
Megan Beetch ◽  
Aline de Conti ◽  
Igor Pogribny
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Liver Cancer ◽  
Regulation Of Gene Expression ◽  
Cancer Development ◽  
Control Group ◽  
Choline Deficiency ◽  
Deficient Diet ◽  
Development Fund ◽  
Increased Risk

Abstract Objectives Nearly 40% of humans have polymorphisms in genes involved in choline metabolism which makes them prone to developing choline deficiency and increased risk for liver damage and liver cancer. Choline is a source of methyl groups needed for many steps in metabolism and epigenetic regulation of gene expression. Although epigenetic aberrations are known to be induced by choline deficiency, it remains unknown how to reverse the changes and attenuate symptoms. Interestingly, certain dietary compounds such as polyphenols have been demonstrated to reverse aberrant epigenetic patterns and exert anti-cancer action. In the present study, we investigate the effects of pterostilbene (PTS) on liver cancer development in rats fed choline-deficient diet and explore mechanisms underlying these effects. Methods Fischer 344 rats were fed a choline-sufficient (CSAA, healthy control group), a choline-deficient (CDAA, cancer group) L-amino acid-defined diet or a CDAA diet supplemented with PTS (134 mg/kg BW/day) (n = 6 per group). At the end of 52 weeks, analyses of liver nodules and histopathological features were performed followed by genome-wide investigation of gene expression in livers using RNA sequencing. DNA methylation was assessed by pyrosequencing. Results A total of 708 genes were significantly differentially expressed in CDAA + PTS group as compared with CDAA group. Among 351 upregulated genes were Bhmt (4.5-fold), G6pc (3.1-fold), and Aldh1l1 (2.6-fold). These metabolism-related genes were significantly downregulated in CDAA vs. CSAA group and their suppression was associated with liver cancer in previous reports. Among 357 genes found to be significantly downregulated by PTS were strong oncogenes such as Mmp12 (2-fold), Myc (1.9-fold) and Mmp27 (1.8-fold). We found PTS-mediated downregulation of Mmp12, that was a top gene upregulated in CDAA vs. CSAA, coincided with 43% hypermethylation of Mmp12 promoter. Conclusions Our findings demonstrate that PTS-mediated changes in gene expression could correspond to changes in DNA methylation of gene regulatory regions and could at least partially explain the observed attenuation of cancer development due to choline deficiency. Funding Sources UBC VP Academic Award, CFI John. R. Evans Leaders Fund, and BC Knowledge Development Fund granted to BS.

scholarly journals Profile of copper-associated DNA methylation and its association with incident acute coronary syndrome

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Pinpin Long ◽  
Qiuhong Wang ◽  
Yizhi Zhang ◽  
Xiaoyan Zhu ◽  
Kuai Yu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Coronary Syndrome ◽  
Methylation Level ◽  
Meta Analysis ◽  
Regulation Of Gene Expression ◽  
Density Lipoprotein ◽  
Blood Leukocytes ◽  
Coronary Syndrome ◽  
A Genome ◽  
Increased Risk

Abstract Background Acute coronary syndrome (ACS) is a cardiac emergency with high mortality. Exposure to high copper (Cu) concentration has been linked to ACS. However, whether DNA methylation contributes to the association between Cu and ACS is unclear. Methods We measured methylation level at > 485,000 cytosine-phosphoguanine sites (CpGs) of blood leukocytes using Human Methylation 450 Bead Chip and conducted a genome-wide meta-analysis of plasma Cu in a total of 1243 Chinese individuals. For plasma Cu-related CpGs, we evaluated their associations with the expression of nearby genes as well as major cardiovascular risk factors. Furthermore, we examined their longitudinal associations with incident ACS in the nested case-control study. Results We identified four novel Cu-associated CpGs (cg20995564, cg18608055, cg26470501 and cg05825244) within a 5% false discovery rate (FDR). DNA methylation level of cg18608055, cg26470501, and cg05825244 also showed significant correlations with expressions of SBNO2, BCL3, and EBF4 gene, respectively. Higher DNA methylation level at cg05825244 locus was associated with lower high-density lipoprotein cholesterol level and higher C-reactive protein level. Furthermore, we demonstrated that higher cg05825244 methylation level was associated with increased risk of ACS (odds ratio [OR], 1.23; 95% CI 1.02–1.48; P = 0.03). Conclusions We identified novel DNA methylation alterations associated with plasma Cu in Chinese populations and linked these loci to risk of ACS, providing new insights into the regulation of gene expression by Cu-related DNA methylation and suggesting a role for DNA methylation in the association between copper and ACS.

scholarly journals Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Chen Yao ◽  
Roby Joehanes ◽  
Rory Wilson ◽  
Toshiko Tanaka ◽  
Luigi Ferrucci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Dna Methylation ◽  
Cigarette Smoking ◽  
Association Study ◽  
Whole Blood ◽  
Lung Diseases ◽  
Epigenetic Modification ◽  
Blood Gene Expression ◽  
Increased Risk

Abstract Background DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. Results We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. Conclusions Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.

scholarly journals DNA methylation and regulation of gene expression: Guardian of our health

The Nucleus ◽  
2021 ◽  
Author(s):  
Gaurab Aditya Dhar ◽  
Shagnik Saha ◽  
Parama Mitra ◽  
Ronita Nag Chaudhuri
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Regulation Of Gene Expression

Progesterone receptor (PROGINS) polymorphism and the risk of endometrial cancer development

2007 ◽  
Vol 17 (1) ◽  
pp. 229-232 ◽  
Author(s):  
M. G. Junqueira ◽  
I. D.C.G. Da Silva ◽  
N. C. Nogueira-De-Souza ◽  
C. V. Carvalho ◽  
D. B. Leite ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Progesterone Receptor ◽  
Receptor Gene ◽  
Population Based ◽  
Cancer Development ◽  
Control Group ◽  
Cancer Group ◽  
Increased Risk ◽  
Progesterone Receptor Gene ◽  
Risk Modifier

The progesterone receptor gene (PROGINS) has been identified as a risk modifier for benign and malignant gynecological diseases. The present case-control study is to evaluate the role of the PROGINS polymorphisms, as risk factor, for endometrial cancer development and to investigate the association between these genetics variants and clinical/pathologic variables of endometrial cancer. PROGINS polymorphism was examined in a total of 121 patients with endometrial cancer and 282 population-based control subjects, all located at the same area in São Paulo, SP, Brazil. The genotyping of PROGINS polymorphism was determined by polymerase chain reaction. The frequencies of PROGINS polymorphism T1/T1, T1/T2, and T2/T2 were 82.6%, 14.9%, and 2.5% in the endometrial cancer patients and 78.4%, 21.6%, and 0% in the controls, respectively. The χ2 test showed a higher incidence of the T2/T2 genotype in the endometrial cancer group subjects, these results were statistically different (P= 0.012). However, due to the fact that there were no women in the control group showing homozygosis for the allele T2, the correct evaluation of odds ratio could not be properly calculated. Regarding the clinical and pathologic findings observed within the group of patients with endometrial cancer, there was significant correlation between T1/T2 genotype and the presence of myoma (P= 0.048). No correlations were observed among the other variables. These data suggest that the PROGINS polymorphism T2/T2 genotype might be associated with an increased risk of endometrial cancer.

Abstract 130: Hypercholesterolemia Suppresses Carotid Artery Endothelial NOS3 Expression via Epigenetic Mechanisms

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Alex Sotolongo ◽  
Yi-Zhou Jiang ◽  
John Karanian ◽  
William Pritchard ◽  
Peter Davies
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Endothelial Cells ◽  
Dna Methyltransferase ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat

Objective: One of the first clinically detectable changes in the vasculature during atherogenesis is the accumulation of cholesterol within the vessel wall. Hypercholesterolemia is characterized by dysfunctional endothelial-dependent vessel relaxation and impaired NOS3 function. Since DNA methylation at gene promoter regions strongly suppresses gene expression, we postulated that high-fat/high-cholesterol diet suppresses endothelial NOS3 through promoter DNA methylation. Methods: Domestic male pigs were fed control diet (CD) or isocaloric high fat and high cholesterol diet (HC; 12% fat and 1.5% cholesterol) for 2, 4, 8 or 12 weeks prior to tissue collection. Furthermore, to determine the effects of risk factor withdrawal, an additional group of swine received HC for 12 weeks and then CD for 8 weeks; a control group received HC continuously for 20 weeks. Endothelial cells were harvested from common carotid aorta. In parallel in vitro studies, cultured human aortic endothelial cells (HAEC) were treated with human LDL, GW3956 (LXR agonist) and RG108 (DNA methyltransferase [DNMT] inhibitor). In cells from both sources, DNA methylation at the NOS3 promoter was measured using methylation specific pyro sequencing, and endothelial gene expression was measured using RT PCR. Results: HC diet increased plasma cholesterol level from 75 mg/dl on CD to a plateau of about 540 mg/dl within 2 weeks. Endothelial NOS3 expression was significantly reduced (71±9 % of CD) after 4 weeks of HC, a level sustained at subsequent time points. Withdrawal of HC for 8 weeks did not recover NOS3 expression. After 12-week HC, the NOS3 promoter was hypermethylated. Withdrawal of HC did not reverse NOS3 promoter methylation. In vitro treatment of HAEC with human LDL (200 mg/dl total cholesterol) or GW3956 (5μM) suppressed NOS3 mRNA to 50% and 30% respectively, suggesting that LXR/RXR is involved in suppression of NOS3. Nitric oxide production was consistently suppressed by GW3959. Both could be reversed through inhibition of DNMTs by RG108. Conclusions: DNA methylation and LXR/RXR pathway can mediate the HC-suppression of endothelial NOS3. The study identifies novel pharmaceutical targets in treating endothelial dysfunction. Crosstalk between these pathways is under investigation.

Acute Exercise Increases the Expression of KIR2DS4 by Promoter Demethylation in NK Cells

2018 ◽  
Vol 40 (01) ◽  
pp. 62-70 ◽  
Author(s):  
Alexander Schenk ◽  
Walter Pulverer ◽  
Christine Koliamitra ◽  
Claus Bauer ◽  
Suzana Ilic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Nk Cells ◽  
Promoter Methylation ◽  
Acute Exercise ◽  
Nk Cell ◽  
Epigenetic Modifications ◽  
Control Group ◽  
Chronic Exercise ◽  
Positive Effects

AbstractPositive effects of exercise on cancer prevention and progression have been proposed to be mediated by stimulating natural killer (NK) cells. Because NK cell receptors are regulated by epigenetic modifications, we investigated whether acute aerobic exercise and training change promoter DNA methylation and gene expression of the activating KIR2DS4 and the inhibiting KIR3DL1 gene. Sixteen healthy women (50–60 years) performed a graded exercise test (GXT) and were randomized into either a passive control group or an intervention group performing a four-week endurance exercise intervention. Blood samples (pre-, post-GXT and post-training) were used for isolation of DNA/RNA of NK cells to assess DNA promoter methylation by targeted deep-amplicon sequencing and gene expression by qRT-PCR. Potential changes in NK cell subsets were determined by flow cytometry. Acute and chronic exercise did not provoke significant alterations of NK cell proportions. Promoter methylation decreased and gene expression increased for KIR2DS4 after acute exercise. A high gene expression correlated with a low methylation of CpGs that were altered by acute exercise. Chronic exercise resulted in a minor decrease of DNA methylation and did not alter gene expression. Acute exercise provokes epigenetic modifications, affecting the balance between the activating KIR2DS4 and the inhibiting KIR3DL1, with potential benefits on NK cell function.

scholarly journals TET2 coactivates gene expression through demethylation of enhancers

2018 ◽  
Vol 4 (11) ◽  
pp. eaau6986 ◽  
Author(s):  
Lu Wang ◽  
Patrick A. Ozark ◽  
Edwin R. Smith ◽  
Zibo Zhao ◽  
Stacy A. Marshall ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Regulation Of Gene Expression ◽  
Estrogen Receptor Α ◽  
Dna Demethylation ◽  
Estrogen Response ◽  
Dna Base ◽  
Modified Dna ◽  
Global Increase ◽  
Methylation Patterns

The tet methylcytosine dioxygenase 2 (TET2) enzyme catalyzes the conversion of the modified DNA base 5-methylcytosine to 5-hydroxymethylcytosine. TET2 is frequently mutated or dysregulated in multiple human cancers, and loss of TET2 is associated with changes in DNA methylation patterns. Here, using newly developed TET2-specific antibodies and the estrogen response as a model system for studying the regulation of gene expression, we demonstrate that endogenous TET2 occupies active enhancers and facilitates the proper recruitment of estrogen receptor α (ERα). Knockout of TET2 by CRISPR-CAS9 leads to a global increase of DNA methylation at enhancers, resulting in attenuation of the estrogen response. We further identified a positive feedback loop between TET2 and ERα, which further requires MLL3 COMPASS at these enhancers. Together, this study reveals an epigenetic axis coordinating a transcriptional program through enhancer activation via DNA demethylation.

scholarly journals Oxidative stress underlies heritable impacts of paternal cigarette smoke exposure

2019 ◽  
Author(s):  
Patrick J Murphy ◽  
Jingtao Guo ◽  
Timothy G Jenkins ◽  
Emma R James ◽  
John R Hoidal ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Dna Methylation ◽  
Cigarette Smoke ◽  
Cigarette Smoke Exposure ◽  
Epigenetic Changes ◽  
Sperm Dna ◽  
Increased Risk ◽  
Paternal Smoking ◽  
Sperm Dna Methylation

SUMMARYPaternal cigarette smoke (CS) exposure is associated with increased risk of behavioral disorders and cancer in offspring, but the mechanism has not been identified. This study used mouse models to evaluate: 1) what impact paternal CS exposure has on sperm DNA methylation (DNAme), 2) whether sperm DNAme changes persist after CS exposure ends, 3) the degree to which DNAme and gene expression changes occur in offspring and 4) the mechanism underlying impacts of CS exposure. We demonstrate that CS exposure induces sperm DNAme changes that are partially corrected within 28 days of removal from CS exposure. Additionally, paternal smoking causes changes in neural DNAme and gene expression in offspring. Remarkably, the effects of CS exposure are largely recapitulated in oxidative stress-compromised Nrf2-/- mice and their offspring, independent of paternal smoking. These results demonstrate that paternal CS exposure impacts offspring phenotype and that oxidative stress underlies CS induced heritable epigenetic changes.

scholarly journals Early Pregnancy Exposure to Ambient Air Pollution among Late-Onset Preeclamptic Cases Is Associated with Placental DNA Hypomethylation of Specific Genes and Slower Placental Maturation

Toxics ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 338
Author(s):  
Karin Engström ◽  
Yumjirmaa Mandakh ◽  
Lana Garmire ◽  
Zahra Masoumi ◽  
Christina Isaxon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Air Pollution ◽  
Early Pregnancy ◽  
Late Onset ◽  
Dispersion Model ◽  
Ambient Air ◽  
Ambient Air Pollution ◽  
Dna Hypomethylation ◽  
Increased Risk

Exposure to ambient air pollution during pregnancy has been associated with an increased risk of preeclampsia (PE). Some suggested mechanisms behind this association are changes in placental DNA methylation and gene expression. The objective of this study was to identify how early pregnancy exposure to ambient nitrogen oxides (NOx) among PE cases and normotensive controls influence DNA methylation (EPIC array) and gene expression (RNA-seq). The study included placentas from 111 women (29 PE cases/82 controls) in Scania, Sweden. First-trimester NOx exposure was assessed at the participants’ residence using a dispersion model and categorized via median split into high or low NOx. Placental gestational epigenetic age was derived from the DNA methylation data. We identified six differentially methylated positions (DMPs, q < 0.05) comparing controls with low NOx vs. cases with high NOx and 14 DMPs comparing cases and controls with high NOx. Placentas with female fetuses showed more DMPs (N = 309) than male-derived placentas (N = 1). Placentas from PE cases with high NOx demonstrated gestational age deceleration compared to controls with low NOx (p = 0.034). No differentially expressed genes (DEGs, q < 0.05) were found. In conclusion, early pregnancy exposure to NOx affected placental DNA methylation in PE, resulting in placental immaturity and showing sexual dimorphism.

Abstract 500: DNA Methylation Profiling Reveals an Epithelial/Endothelial-Mesenchymal Transition-like Signature of Intima-Media Cells in the Ascending Aorta of Bicuspid Aortic Valve Patients

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Hanna M Björck ◽  
Lei Du ◽  
Valentina Paloschi ◽  
Shohreh Maleki ◽  
Silvia Pulignani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Epithelial Mesenchymal Transition ◽  
Ascending Aorta ◽  
Molecular Signature ◽  
Aortic Valves ◽  
Global Methylation ◽  
Mesenchymal Transition ◽  
Differentially Methylated Genes ◽  
Increased Risk

Introduction: Individuals with bicuspid aortic valves (BAV) are at increased risk of ascending aortic aneurysm than individuals with tricuspid aortic valves (TAV), but the underlying mechanism is not fully understood. Aberrant DNA methylation has been described in various human diseases, and we have shown that key enzymes in the methylation machinery are differentially expressed in the aortic intima-media of BAV and TAV patients. In the present study, we assessed the hypothesis that DNA methylation may play an important role during aneurysm formation in BAV. We undertook a global methylation approach to delineate biological processes associated with BAV aortopathy, using TAV as a reference. Methods: Ascending aortic biopsies were collected from 21 BAV and 24 TAV patients, with either a non-dilated or a dilated aorta, at the time of surgery. Global DNA methylation was measured in the intima-media layer using Illumina 450k Array. Gene expression was analyzed in the same samples using Affymetrix Exon Array. Results: Compared with TAV, the BAV dilated aorta was hypomethylated (P=0.031), correlating with an up-regulation of global gene expression. A total of 4913 differentially methylated regions (DMRs) were identified and Hallmark analysis of the DMR-associated genes with a fold change of 10% (n=3147) showed a gene signature of Epithelial Mesenchymal Transition (EMT) (FDR q=2.91e-29). This was further confirmed by functional annotation analysis of hypomethylated DMRs using the Genomic Regions Enrichment of Annotations Tool (Stanford University), showing association to actin filament bundle (P=7.09e-12), stress fibers (P=1.72e-11) and adherence junctions (P=2.97e-8). Interestingly, analysis of non-dilated BAV and TAV aorta revealed that genes involved in EMT were the most differentially methylated genes prior to dilatation (FDR q=1.18e-6). We further confirmed the EMT-related molecular signature by immunostaining of some key players of EMT. In conclusion, epigenetic profiling clearly revealed differential methylation between BAV and TAV aorta, particularly in EMT-related genes. Aberrant EMT in the ascending aorta prior to dilatation may constitute the basis for the increased aneurysm susceptibility in BAV patients.

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