scholarly journals Postnatal Smoke Exposure Further Increases the Hepatic Nicotine Metabolism in Prenatally Smoke Exposed Male Offspring and Is Linked with Aberrant Cyp2a5 Methylation

2020 ◽  
Vol 22 (1) ◽  
pp. 164
Author(s):  
Khosbayar Lkhagvadorj ◽  
Zhijun Zeng ◽  
Karolin F. Meyer ◽  
Laura P. Verweij ◽  
Wierd Kooistra ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Mrna Expression ◽  
Nicotine Dependence ◽  
Susceptibility Gene ◽  
Smoke Exposure ◽  
Adverse Outcomes ◽  
Male Offspring ◽  
Adult Offspring ◽  
Mrna Levels ◽  
Nicotine Metabolism

Prenatal smoke exposure (PreSE) is a risk factor for nicotine dependence, which is further enhanced by postnatal smoke exposure (PostSE). One susceptibility gene to nicotine dependence is Cytochrome P450 (CYP) 2A6, an enzyme responsible for the conversion of nicotine to cotinine in the liver. Higher CYP2A6 activity is associated with nicotine dependence and could be regulated through DNA methylation. In this study we investigated whether PostSE further impaired PreSE-induced effects on nicotine metabolism, along with Cyp2a5, orthologue of CYP2A6, mRNA expression and DNA methylation. Using a mouse model where prenatally smoke-exposed adult offspring were exposed to cigarette smoke for 3 months, enzyme activity, mRNA levels, and promoter methylation of hepatic Cyp2a5 were evaluated. We found that in male offspring, PostSE increased PreSE-induced cotinine levels and Cyp2a5 mRNA expression. In addition, both PostSE and PreSE changed Cyp2a5 DNA methylation in male groups. PreSE however decreased cotinine levels whereas it had no effect on Cyp2a5 mRNA expression or methylation. These adverse outcomes of PreSE and PostSE were most prominent in males. When considered in the context of the human health aspects, the combined effect of prenatal and adolescent smoke exposure could lead to an accelerated risk for nicotine dependence later in life.

DDR1 methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes

Epigenomics ◽  
2021 ◽  
Author(s):  
Beatriz Garcia-Ruiz ◽  
Manuel Castro de Moura ◽  
Gerard Muntané ◽  
Lourdes Martorell ◽  
Elena Bosch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Bipolar Disorder ◽  
Mrna Expression ◽  
Gene Expression Analysis ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Genome Wide ◽  
Isoform Expression

Aim: To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes. Materials & methods: Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. Results: DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes. Conclusion: DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.

Maternal glucocorticoid treatment programs HPA regulation in adult offspring: sex-specific effects

2001 ◽  
Vol 280 (5) ◽  
pp. E729-E739 ◽  
Author(s):  
Li Liu ◽  
Antai Li ◽  
Stephen G. Matthews
Keyword(s):  
Guinea Pigs ◽  
Plasma Cortisol ◽  
In Utero ◽  
Adult Brain ◽  
Male Offspring ◽  
Treatment Programs ◽  
Adult Offspring ◽  
Mrna Levels ◽  
Glucocorticoid Treatment ◽  
Cortisol Levels

Pregnant guinea pigs were treated with dexamethasone (1 mg/kg) or vehicle on days 40–41, days 50–51, and days 60–61 of gestation. Adult offspring were split into two groups. Group 1 guinea pigs were catheterized, and the hypothalamo-pituitary-adrenal (HPA) axis was tested in basal and activated states. Group 2 guinea pigs were euthanized with no further manipulation. In male offspring, prenatal dexamethasone exposure resulted in a significant reduction in brain-to-body weight ratio. Dexamethasone-exposed male offspring exhibited reduced basal and activated plasma cortisol levels, which was associated with elevated hippocampal mineralocorticoid receptor (MR) mRNA and increased plasma testosterone. In females exposed to glucocorticoids in utero, basal and stimulated plasma cortisol levels were higher in the follicular and early luteal phases of the cycle, but this effect was reversed in the late luteal phase, indicating a significant interaction of sex steroids. In female offspring (at estrus), glucocorticoid receptor mRNA levels were lower in the paraventricular nucleus and pars distalis but higher in the hippocampus in animals exposed to dexamethasone in utero. Hippocampal MR mRNA levels were significantly lower (∼50%) than in controls. In conclusion, repeated antenatal glucocorticoid treatment programs HPA function in a sex-specific manner, and these changes are associated with modification of corticosteroid receptor expression in the adult brain and pituitary.

scholarly journals Molecular and immune correlates of TIM-3 (HAVCR2) and galectin 9 (LGALS9) mRNA expression and DNA methylation in melanoma

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Tobias A. W. Holderried ◽  
Luka de Vos ◽  
Emma Grace Bawden ◽  
Timo J. Vogt ◽  
Joern Dietrich ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Overall Survival ◽  
Mrna Expression ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Inverse Correlation ◽  
Mrna Levels ◽  
Cpg Sites ◽  
Immune Correlates ◽  
Strong Inverse Correlation

Abstract Background The T cell immunoglobulin and mucin-domain containing-3 receptor TIM-3 (also known as hepatitis A virus cellular receptor 2, encoded by HAVCR2) and its ligand galectin 9 (LGALS9) are promising targets for immune checkpoint inhibition immunotherapies. However, little is known about epigenetic regulation of the encoding genes. This study aimed to investigate the association of TIM-3 and LGALS9 DNA methylation with gene expression, patients’ survival, as well as molecular and immune correlates in malignant melanoma. Results Methylation of all six TIM-3 CpGs correlated significantly with TIM-3 mRNA levels (P ≤ 0.05). A strong inverse correlation (Spearman’s ρ = − 0.49) was found in promoter regions, while a strong positive correlation (ρ = 0.63) was present in the gene body of TIM-3. High TIM-3 mRNA expression (hazard ratio (HR) = 0.88, 95% confidence interval (CI) [0.81–0.97], P = 0.007) was significantly associated with better overall survival. Seven of the eight LGALS9 CpG sites correlated significantly with LGALS9 mRNA levels (P ≤ 0.003). Methylation at five CpG sites showed a strong inverse correlation (Spearman’s ρ = − 0.67) and at two sites a weak positive correlation (Spearman’s ρ = 0.15). High LGALS9 mRNA expression was significantly associated with increased overall survival (HR = 0.83, 95%CI [0.75–0.93], P = 0.001). In addition, we found significant correlations between TIM-3 and LGALS9 methylation and mRNA expression with immune cell infiltrates and significant differences among distinct immune cell subsets. Conclusions Our study points toward an epigenetic regulation of TIM-3 and LGALS9 via DNA methylation and might provide an avenue for the development of a predictive biomarker for response to immune checkpoint blockade.

scholarly journals Prenatal exposure to tobacco smoke sex dependently influences methylation and mRNA levels of the Igf axis in lungs of mouse offspring

2017 ◽  
Vol 312 (4) ◽  
pp. L542-L555 ◽  
Author(s):  
K. F. Meyer ◽  
S. Krauss-Etschmann ◽  
W. Kooistra ◽  
M. Reinders-Luinge ◽  
W. Timens ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Body Weight ◽  
Prenatal Exposure ◽  
Promoter Methylation ◽  
Lung Development ◽  
Smoke Exposure ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Site Specific ◽  
Cpg Site

Prenatal smoke exposure is a risk factor for abnormal lung development and increased sex-dependent susceptibility for asthma and chronic obstructive pulmonary disease (COPD). Birth cohort studies show genome-wide DNA methylation changes in children from smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. The insulin-like growth factor (IGF) system plays an important role in lung development. We hypothesized that prenatal exposure to smoke induces lasting changes in promoter methylation patterns of Igf1 and Igf1r, thus influencing transcriptional activity and contributing to abnormal lung development. We measured and compared mRNA levels along with promoter methylation of Igf1 and Igf1r and their protein concentrations in lung tissue of 30-day-old mice that had been prenatally exposed to cigarette smoke (PSE) or filtered air (control). Body weight at 30 days after birth was measured as global indicator of normal development. Female PSE mice showed lower mRNA levels of Igf1 and its receptor ( Igf1: P = 0.05; Igf1r: P = 0.03). Furthermore, CpG-site-specific methylation changes were detected in Igf1r in a sex-dependent manner and the body weight of female offspring was reduced after prenatal exposure to smoke, while protein concentrations were unaffected. Prenatal exposure to smoke induces a CpG-site-specific loss of Igf1r promoter methylation, which can be associated with body weight. These findings highlight the sex-dependent and potentially detrimental effects of in utero smoke exposure on DNA methylation and Igf1 and Igf1r mRNA levels. The observations support a role for Igf1 and Igf1r in abnormal development.

scholarly journals Prenatal smoke exposure induces persistent Cyp2a5 methylation and increases nicotine metabolism in the liver of neonatal and adult male offspring

Epigenetics ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. 1370-1385 ◽  
Author(s):  
Khosbayar Lkhagvadorj ◽  
Karolin F. Meyer ◽  
Laura P. Verweij ◽  
Wierd Kooistra ◽  
Marjan Reinders-Luinge ◽  
...  
Keyword(s):  
Adult Male ◽  
Smoke Exposure ◽  
Male Offspring ◽  
Nicotine Metabolism

scholarly journals Analysis of mRNA Expression and DNA Methylation Datasets According to the Genomic Distribution of CpG Sites in Osteoarthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Yi ◽  
Xiongfeng Xu ◽  
Jiawei Yao ◽  
Bo Qiu
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Mrna Expression ◽  
Signaling Pathway ◽  
Regulation Of Gene Expression ◽  
Enrichment Analysis ◽  
Integrated Analysis ◽  
Mrna Levels ◽  
Combined Analysis ◽  
Transcriptional Changes

Abstract Objectives Transcriptional changes in cartilage can impact function by causing degradation such as that which occurs during the development of osteoarthritis (OA). Epigenetic regulation may be a key factor leading to transcriptional changes in OA. In this study, we performed a combined analysis of DNA methylation and gene expression microarray datasets and identified key transcription factors (TFs) central to the regulation of gene expression in OA. Methods A DNA methylation profile dataset (GSE63106) and a gene expression profiling dataset (GSE114007) were extracted from the Gene Expression Omnibus (GEO). We used ChAMP methylation analysis and the Limma package to identify differentially methylation genes (DMGs) and differentially expressed genes (DEGs) from normal and human knee cartilage samples in OA. Function enrichment analysis of DMGs was conducted using the DAVID database. A combined analysis of DEGs and DMGs was conducted to identify key TFs in OA. We then validated the mRNA expression of selected TFs in normal and OA cartilage by RT-qPCR. Primary chondrocytes were cultured and treated with the DNA methylation inhibitor 5-Aza-2-deoxycytidine (5-Aza) for functional validation. Results We identified 2,170 differential methylation sites (DMS) containing 1005 genes and 1986 DEGs between normal human and OA cartilage. Functional analysis of DMGs revealed that focal adhesion, extracellular matrix (ECM)-receptor interactions, the PI3K-Akt signaling pathway, and the FoxO signaling pathway were involved in OA. Integrated analysis showed a subset of 17 TFs. Four TFs (ELF3, SOX11, RARA, and FOXD2) were validated. RT-qPCR results showed the mRNA expression of SOX11, RARA, and FOXD2 were consistent with the results from the mRNA expression data. However, the expression of ELF3 could not be validated. Upon 5-Aza-2′-deoxycytidine (5-Aza) treatment, the mRNA levels of ELF3 and SOX11 were down-regulated, whilst RARA was up-regulated, and FOXD2 showed no significant change in expression level. Conclusions the effect of DNA methylation on the transcriptional regulation is related to the distribution of methylated sites across the genome. Epigenetic studies on the positions of DMS in transcriptional units can inform a better understanding of the function of DNA methylation and its transcription regulation.

scholarly journals Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 41
Author(s):  
Nouf Aljobaily ◽  
Michael J. Viereckl ◽  
David S. Hydock ◽  
Hend Aljobaily ◽  
Tsung-Yen Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Methylation ◽  
Body Weight ◽  
Liver Fibrosis ◽  
Liver Damage ◽  
Cellular Senescence ◽  
Weight Ratio ◽  
Mrna Levels ◽  
Body Weight Ratio ◽  
Chromosomal Stability

Background: Treatment with the chemotherapy drug doxorubicin (DOX) may lead to toxicities that affect non-cancer cells including the liver. Supplementing the diet with creatine (Cr) has been suggested as a potential intervention to minimize DOX-induced side effects, but its effect in alleviating DOX-induced hepatoxicity is currently unknown. Therefore, we aimed to examine the effects of Cr supplementation on DOX-induced liver damage. Methods: Male Sprague-Dawley rats were fed a diet supplemented with 2% Cr for four weeks, 4% Cr for one week followed by 2% Cr for three more weeks, or control diet for four weeks. Animals then received either a bolus i.p. injection of DOX (15 mg/kg) or saline as a placebo. Animals were then sacrificed five days-post injection and markers of hepatoxicity were analyzed using the liver-to-body weight ratio, aspartate transaminase (AST)-to- alanine aminotransferase (ALT) ratio, alkaline phosphatase (ALP), lipemia, and T-Bilirubin. In addition, hematoxylin and eosin (H&E) staining, Picro-Sirius Red staining, and immunofluorescence staining for CD45, 8-OHdG, and β-galactosidase were performed to evaluate liver morphology, fibrosis, inflammation, oxidative stress, and cellular senescence, respectively. The mRNA levels for biomarkers of liver fibrosis, inflammation, oxidative stress, and senescence-related genes were measured in liver tissues. Chromosomal stability was evaluated using global DNA methylation ELISA. Results: The ALT/AST ratio and liver to body weight ratio tended to increase in the DOX group, and Cr supplementation tended to attenuate this increase. Furthermore, elevated levels of liver fibrosis, inflammation, oxidative stress, and senescence were observed with DOX treatment, and Cr supplementation prior to DOX treatment ameliorated this hepatoxicity. Moreover, DOX treatment resulted in chromosomal instability (i.e., altered DNA methylation profile), and Cr supplementation showed a tendency to restore chromosomal stability with DOX treatment. Conclusion: The data suggest that Cr protected against DOX-induced hepatotoxicity by attenuating fibrosis, inflammation, oxidative stress, and senescence.

scholarly journals Reprogramming mRNA Expression in Response to Defect in RNA Polymerase III Assembly in the Yeast Saccharomyces cerevisiae

2021 ◽  
Vol 22 (14) ◽  
pp. 7298
Author(s):  
Izabela Rudzińska ◽  
Małgorzata Cieśla ◽  
Tomasz W. Turowski ◽  
Alicja Armatowska ◽  
Ewa Leśniewska ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Ribosome Biogenesis ◽  
Rna Polymerase Iii ◽  
Mrna Levels ◽  
Rna Seq ◽  
Yeast Saccharomyces Cerevisiae ◽  
Protein Coding ◽  
General Transcription Factor ◽  
Pol I ◽  
Pol Iii

The coordinated transcription of the genome is the fundamental mechanism in molecular biology. Transcription in eukaryotes is carried out by three main RNA polymerases: Pol I, II, and III. One basic problem is how a decrease in tRNA levels, by downregulating Pol III efficiency, influences the expression pattern of protein-coding genes. The purpose of this study was to determine the mRNA levels in the yeast mutant rpc128-1007 and its overdose suppressors, RBS1 and PRT1. The rpc128-1007 mutant prevents assembly of the Pol III complex and functionally mimics similar mutations in human Pol III, which cause hypomyelinating leukodystrophies. We applied RNAseq followed by the hierarchical clustering of our complete RNA-seq transcriptome and functional analysis of genes from the clusters. mRNA upregulation in rpc128-1007 cells was generally stronger than downregulation. The observed induction of mRNA expression was mostly indirect and resulted from the derepression of general transcription factor Gcn4, differently modulated by suppressor genes. rpc128-1007 mutation, regardless of the presence of suppressors, also resulted in a weak increase in the expression of ribosome biogenesis genes. mRNA genes that were downregulated by the reduction of Pol III assembly comprise the proteasome complex. In summary, our results provide the regulatory links affected by Pol III assembly that contribute differently to cellular fitness.

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