Maternal folic acid depletion during early pregnancy increases sensitivity to squamous tumor formation in the offspring in mice

2019 ◽  
Vol 10 (6) ◽  
pp. 683-691
Author(s):  
Tomoyo Kawakubo-Yasukochi ◽  
Masahiko Morioka ◽  
Kenji Ohe ◽  
Atsushi Yasukochi ◽  
Yasuhiko Ozaki ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Folic Acid ◽  
Early Pregnancy ◽  
Promoter Region ◽  
Methylation Status ◽  
Tumor Formation ◽  
The Third ◽  
Future Risk ◽  
Lifestyle Related Diseases ◽  
First Time

AbstractGestational nutrition is widely recognized to affect an offspring’s future risk of lifestyle-related diseases, suggesting the involvement of epigenetic mechanisms. As folic acid (FA) is a nutrient essential for modulating DNA methylation, we sought to determine how maternal FA intake during early pregnancy might influence tumor sensitivity in an offspring. Dams were maintained on a FA-depleted (FA(−)) or normal (2 mg FA/kg; FA(+)) diet from 2 to 3 days before mating to 7 days post-conception, and their offspring were challenged with chemical tumorigenesis using 7,12-dimethylbenz[a)anthracene and phorbol 12-myristate 13-acetate for skin and 4-nitroquinoline N-oxide for tongue. In both squamous tissues, tumorigenesis was more progressive in the offspring from FA(−) than FA(+) dams. Notably, in the skin of FA(−) offspring, the expression and activity of cylindromatosis (Cyld) were decreased due to the altered DNA methylation status in its promoter region, which contributed to increased tumorigenesis coupled with inflammation in the FA(−) offspring. Thus, we conclude that maternal FA insufficiency during early pregnancy is able to promote neoplasm progression in the offspring through modulating DNA methylation, such as Cyld. Moreover, we propose, for the first time, “innate” utero nutrition as the third cause of tumorigenesis besides the known causes—hereditary predisposition and acquired environmental factors.

scholarly journals Correlation of methylation status in MTHFR promoter region with recurrent pregnancy loss

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mai Mahmoud Shaker ◽  
Taghreed Abdelmoniem shalabi ◽  
Khalda said Amr
Keyword(s):  
Dna Methylation ◽  
Dna Sequences ◽  
Promoter Region ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Methylation Status ◽  
Control Group ◽  
Case Group ◽  
Methyl Radical ◽  
Fertile Women

Abstract Background DNA methylation is an epigenetic process for modifying transcription factors in various genes. Methylenetetrahydrofolate reductase (MTHFR) stimulates synthesis of methyl radical in the homocysteine cycle and delivers methyl groups needed in DNA methylation. Furthermore, numerous studies have linked gene polymorphisms of this enzyme with a larger risk of recurrent pregnancy loss (RPL), yet scarce information is available concerning the association between epigenetic deviations in this gene and RPL. Hypermethylation at precise DNA sequences can function as biomarkers for a diversity of diseases. We aimed by this study to evaluate the methylation status of the promoter region of MTHFR gene in women with RPL compared to healthy fertile women. It is a case–control study. Hundred RPL patients and hundred healthy fertile women with no history of RPL as controls were recruited. MTHFR C677T was assessed by polymerase chain reaction-restriction fragment length polymorphism (RFLP). Quantitative evaluation of DNA methylation was performed by high-resolution melt analysis by real-time PCR. Results The median of percentage of MTHFR promoter methylation in RPL cases was 6.45 [0.74–100] vs. controls was 4.50 [0.60–91.7], P value < 0.001. In the case group, 57 hypermethylated and 43 normo-methylated among RPL patients vs. 40 hypermethylated and 60 normo-methylated among controls, P< 0.005. Frequency of T allele in C677T MTHFR gene among RPL patients was 29% vs. 23% among the control group; C allele vs. T allele: odds ratio (OR) = 1.367 (95% confidence interval (CI) 0.725–2.581). Conclusion Findings suggested a significant association between hypermethylation of the MTHFR promoter region in RPL patients compared to healthy fertile women.

Study on DNA Methylation Status of WT1 Gene in Its Promoter Region in Hematologic Neoplasm Cell Lines.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4386-4386
Author(s):  
Ye Zhao ◽  
Zi-xing Chen ◽  
Shao-yan Hu ◽  
Jian-nong Cen
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cell Lines ◽  
Promoter Region ◽  
U937 Cell ◽  
Methylation Status ◽  
Gene Promoter ◽  
Epigenetic Mechanism ◽  
Wt1 Gene ◽  
Gene Promoter Region

Abstract The methylation at CpG island in the promoter region of a gene is one of the important epigenetic mechanism which regulates the gene activity. To study the DNA methylation pattern of WT1 gene promoter region within hematologic neoplastic cell lines and its correlation with WT1 gene expression by using the PCR-based methods. RT-PCR and Methylation-specific PCR were performed to study the WT1 gene expression in 8226, HL-60, Jurkat, K562, KG-1, NB4, Raji, SHI-1, U266 and U937 cell lines and the DNA methylation status in promoter region of WT1 gene. After treatment of U937 cell line by 5-aza-CdR, a demethylation inducing agent, the changes of WT1 gene expression level and the methylation status in its promter region in U937 cells was determined. Our Results showed that HL-60, K562, KG-1, NB4, SHI-1 cell lines demonstrated higher level of WT1 expression, while extremely low level was found in 8226, Jurkat, Raji, U266 and U937. The DNA hypermethylation in WT1 gene promoter region was identified in 8226, Jurkat, Raji, U266 and U937 cell lines. The WT1 gene expression in U937 was markedly enhanced after treatment with 5-aza-CdR in company with the decrease of methylated level and the increase of unmethylated level in its promoter region. These results indicate that modulation of the DNA methylation in WT1 promoter region is one of the epigenetic mechanisms to regulate its expression.

Kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) is regulated by DNA methylation

2008 ◽  
Vol 295 (1) ◽  
pp. F165-F170 ◽  
Author(s):  
Masayo Aoki ◽  
Tomohiro Terada ◽  
Moto Kajiwara ◽  
Ken Ogasawara ◽  
Iwao Ikai ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Promoter Region ◽  
Organic Cation ◽  
Methylation Status ◽  
Organic Cation Transporter ◽  
Proximal Promoter ◽  
Specific Expression ◽  
Proximal Promoter Region ◽  
E Box ◽  
Organic Cation Transporter 2

Human organic cation transporter 2 (OCT2/SLC22A2), which is specifically expressed in the kidney, plays critical roles in the renal secretion of cationic compounds. Tissue expression and membrane localization of OCT2 are closely related to the tissue distribution, pharmacological effects, and/or adverse effects of its substrate drugs. However, the molecular mechanisms underlying the kidney-specific expression of OCT2 have not been elucidated. In the present study, therefore, we examined the contribution of DNA methylation of the promoter region for the OCT2 gene to its tissue-specific expression using human tissue samples. In vivo methylation status of the proximal promoter region of OCT2 and that of OCT1, a liver-specific organic cation transporter, were investigated by bisulfite sequencing using human genomic DNA extracted from the kidney and liver. All CpG sites in the OCT2 proximal promoter were hypermethylated in the liver, while hypomethylated in the kidney. On the other hand, the promoter region of OCT1 was hypermethylated in both the kidney and liver. The level of methylation of the OCT2 promoter was especially low at the CpG site in the E-box, the binding site of the basal transcription factor upstream stimulating factor (USF) 1. In vitro methylation of the OCT2 proximal promoter dramatically reduced the transcriptional activity, and an electrophoretic mobility shift assay showed that methylation at the E-box inhibited the binding of USF1. These results indicate that kidney-specific expression of human OCT2 is regulated by methylation of the proximal promoter region, interfering with the transactivation by USF1.

scholarly journals Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation

2021 ◽  
Author(s):  
Yinggang Hua ◽  
Long Li ◽  
Liangliang Cai ◽  
Guoyan Liu
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Promoter Region ◽  
Methylation Status ◽  
Gastric Cancer Cell Line ◽  
Cancer Cell Line ◽  
Annexin V ◽  
Receptor Activation ◽  
Diffuse Gastric Cancer ◽  
Gastric Cancer Cells

Abstract P2RY1 receptor is known to cause cancer by activating the ERK signal pathway, its DNA methylation status or even the corresponding regulatory mechanism remains unknown. In this study, DNA methylation chip was used to profile the genome-wide DNA methylation level in gastric cancer tissues. Proliferation and apoptosis of the SGC7901 gastric cancer cell line were determined after treatment with a selective P2RY1 receptor agonist, MRS2365. The promoter region of P2RY1 was found to be highly methylated with 4 hypermethylated sites (|Δβ value| >0.2) in diffuse gastric cancer and then were validated by bioinformatic analysis in TCGA database. Analysis of MRS2365-treated cells by annexin-V/PI staining and Caspase-3 activity assays indicated the induction of apoptosis in SGC7901 cells. P2RY1 receptor activation in human SGC7901 gastric cancer cells via the MRS2365 agonist induced apoptosis and reduced cell growth. High DNA methylation in the promoter region of P2RY1 may have contributed to the reduced expression of P2RY1’s mRNA, which is likely responsible for the “aggressive” nature of the diffuse type gastric cancer.

scholarly journals Association of Breastfeeding Duration with Susceptibility to Allergy, Influenza, and Methylation Status of TLR1 Gene

Medicina ◽  
2019 ◽  
Vol 55 (9) ◽  
pp. 535
Author(s):  
Ma’mon M. Hatmal ◽  
Nada N. Issa ◽  
Walhan Alshaer ◽  
Hamzeh J. Al-Ameer ◽  
Omar Abuyaman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Promoter Region ◽  
Methylation Status ◽  
Breastfeeding Duration ◽  
Toll Like Receptor ◽  
Chain Reaction ◽  
Blood Samples ◽  
Three Samples ◽  
Gene Level ◽  
Polymerase Chain

Background and Objectives: This study aimed to investigate the possible association between exclusive breastfeeding duration during early infancy and susceptibility to allergy and influenza in adulthood. Furthermore, we also investigated the association of breastfeeding duration with DNA methylation at two sites in the promoter of the toll-like receptor-1 (TLR1) gene, as well as the association between DNA methylation of the toll-like receptor-1 (TLR1) gene and susceptibility to different diseases. Materials and Methods: Blood samples were collected from 100 adults and classified into two groups according to breastfeeding duration (<6 months and ≥6 months) during infancy. Subjects were asked to complete a questionnaire on their susceptibilities to different diseases and sign a consent form separately. Fifty-three samples underwent DNA extraction, and the DNA samples were divided into two aliquots, one of which was treated with bisulfite reagent. The promoter region of the TLR1 gene was then amplified by polymerase chain reaction (PCR) and sequenced. Results: We found a significant association between increased breastfeeding duration and a reduction in susceptibility to influenza and allergy, as well asa significant reduction in DNA methylation within the promoter of the TLR1 gene. No association was found between DNA methylation and susceptibility to different diseases. Conclusions: The findings demonstrate the significance of increased breastfeeding duration for improved health outcomes at the gene level.

Abstract PO-019: DNA methylation status in a promoter region of the K-RAS gene in patients with Colorectal Cancer

2020 ◽  
Author(s):  
Jehison Alirio Herrera-Pulido ◽  
Orlando Ricaurte-Guerrero ◽  
Jinneth Acosta-Forero ◽  
Pablo Moreno-Acosta ◽  
María Carolina Sanabria-Salas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Promoter Region ◽  
Methylation Status ◽  
Ras Gene

scholarly journals Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation

2021 ◽  
Author(s):  
yinggang hua ◽  
yanling liu ◽  
long li ◽  
guoyan liu
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Promoter Region ◽  
Methylation Status ◽  
Diffuse Gastric Cancer ◽  
Normal Tissues ◽  
The Difference ◽  
Diffuse Type Gastric Cancer ◽  
Cancer Tissues ◽  
Erk Signal Pathway

Abstract Background P2RY1 receptor is known to cause cancer by activating the ERK signal pathway, its DNA methylation status or even the corresponding regulatory mechanism remains unknown. Methods In this study, DNA methylation chip was used to profile the genome-wide DNA methylation level in gastric cancer tissues. Then validated by the bioinformatics analysis in the TCGA database, Immunohistochemistry staining data obtained from the HPA database to verify the difference in protein expression between normal tissues and tumor tissues . Results The promoter region of P2RY1 was found to be highly methylated with 4 hypermethylated sites (|Δβ value| >0.2) in diffuse gastric cancer and the expression level of P2RY1 is relatively low compared with non-cancerous tissues. We also showed that MRS2365, a selective agonist of the P2RY1 receptor, can induce phosphorylation of ERK1/2, inhibit cell proliferation/migration and induce apoptosis. Conclusion High DNA methylation in the promoter region of P2RY1 may have contributed to the reduced expression of P2RY1’s mRNA, which is likely responsible for the “aggressive” nature of the diffuse type gastric cancer.

scholarly journals Timing- and Dose-Specific Associations of Prenatal Smoke Exposure With Newborn DNA Methylation

2020 ◽  
Vol 22 (10) ◽  
pp. 1917-1922
Author(s):  
Giulietta S Monasso ◽  
Vincent W V Jaddoe ◽  
Johan C de Jongste ◽  
Liesbeth Duijts ◽  
Janine F Felix
Keyword(s):  
Dna Methylation ◽  
Early Pregnancy ◽  
Maternal Smoking ◽  
Third Trimester ◽  
Smoking During Pregnancy ◽  
The Third ◽  
Quitting Smoking ◽  
Maternal Smoking During Pregnancy ◽  
Paternal Smoking ◽  
In Pregnancy

Abstract Introduction Fetal changes in DNA methylation may underlie associations of maternal smoking during pregnancy with adverse outcomes in children. We examined critical periods and doses of maternal smoking during pregnancy in relation to newborn DNA methylation, and associations of paternal smoking with newborn DNA methylation. Aims and Methods This study was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We assessed parental smoking during pregnancy using questionnaires. We analyzed associations of prenatal smoke exposure with newborn DNA methylation at 5915 known maternal smoking-related cytosine-phosphate-guanine sites (CpGs) in 1261 newborns using linear regression. Associations with false discovery rate-corrected p-values &lt; .05 were taken forward. Results Sustained maternal smoking was associated with newborn DNA methylation at 1391 CpGs, compared with never smoking. Neither quitting smoking early in pregnancy nor former smoking was associated with DNA methylation, compared with never smoking. Among sustained smokers, smoking ≥5, compared with &lt;5, cigarettes/d was associated with DNA methylation at seven CpGs. Paternal smoking was not associated with DNA methylation, independent of maternal smoking status. Conclusions Our results suggest that CpGs associated with sustained maternal smoking are not associated with maternal smoking earlier in pregnancy or with paternal smoking. Some of these CpGs show dose–response relationships with sustained maternal smoking. The third trimester may comprise a critical period for associations of smoking with newborn DNA methylation, or sustained smoking may reflect higher cumulative doses. Alternatively, maternal smoking limited to early pregnancy and paternal smoking may be associated with DNA methylation at specific other CpGs not studied here. Implications Our results suggest that quitting maternal smoking before the third trimester of pregnancy, and possibly lowering smoking dose, may prevent differential DNA methylation in the newborns at CpGs associated with sustained smoking. If the relevance of DNA methylation for clinical outcomes is established, these results may help in counseling parents-to-be about quitting smoking.

scholarly journals DNA Methylation Regulates Placental Lactogen I Gene Expression

Endocrinology ◽  
2001 ◽  
Vol 142 (8) ◽  
pp. 3389-3396 ◽  
Author(s):  
Jae-Hyeon Cho ◽  
Hiromichi Kimura ◽  
Tatsuya Minami ◽  
Jun Ohgane ◽  
Naka Hattori ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Promoter Region ◽  
Trichostatin A ◽  
Methylation Status ◽  
Placental Lactogen ◽  
Specific Gene ◽  
Tissue Specific ◽  
Reporter Activity ◽  
I Gene

Abstract Expression of rat placental lactogen I is specific to the placenta and never expressed in other tissues. To obtain insight into the mechanism of tissue-specific gene expression, we investigated the methylation status in 3.4 kb of the 5′-flanking region of the rat placental lactogen I gene. We found that the distal promoter region of the rat placental lactogen I gene had more potent promoter activity than that of the proximal area alone, which contains several possible cis-elements. Although there are only 17 CpGs in the promoter region, in vitro methylation of the reporter constructs caused severe suppression of reporter activity, and CpG sites in the placenta were more hypomethylated than other tissues. Coexpression of methyl-CpG-binding protein with reporter constructs elicited further suppression of the reporter activity, whereas treatment with trichostatin A, an inhibitor of histone deacetylase, reversed the suppression caused by methylation. Furthermore, treatment of rat placental lactogen I nonexpressing BRL cells with 5-aza-2′-deoxycytidine, an inhibitor of DNA methylation, or trichostatin A resulted in the de novo expression of rat placental lactogen I. These results provide evidence that change in DNA methylation is the fundamental mechanism regulating the tissue-specific expression of the rat placental lactogen I gene.

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