Hypermethylated CpG Sites in the
            <i>MTR</i>
            Gene Promoter in Preterm Placenta

Khot, Vinita; Yadav, Dilip Kumar; Shrestha, Smeeta; Kaur, Lovejeet; Sundrani, Deepali; Chavan‐Gautam, Preeti; Mehendale, Savita; Chandak, Giriraj Ratan; Joshi, Sadhana

doi:10.2217/epi-2016-0173

Cited by 13 publications

(10 citation statements)

References 51 publications

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“…It is well known that cell division and differentiation during embryogenesis are in control of various growth factors and hormones which are regulated by these vitamins (Gluckman and Pinal, 2003). Independent studies report that high folate disturbs dietary protein metabolism and disturbs the flux of DNA methylation; and these aberrant changes are linked to adverse pregnancy outcomes like preterm births and low birth weight (Achón et al, 2000;Khot, Yadav, Shrestha, Kaur, Sundrani, Chavan-Gautam, Mehendale, Chandak and Joshi, 2017). This further strengthens the observation in the present study that high folate, in B12 deficiency, might be causing overall nutritional insults in the feto-placental unit and thus perturbing the viability of the fetus, resulting in pregnancy losses.…”

Section: Resultsmentioning

confidence: 99%

Recurrent pregnancy lossesvis-à-visanemia and vitamin (Folate/B12) imbalance

Kaur

Puri

Saraswathy

et al. 2018

IJHG

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Purpose Recurrent pregnancy losses (RPL), a major contributor of reproductive wastage, affect maternal health both physically and mentally. Folate and B12 (Vitamin B12) deficiency anemia is common in the reproductive age group women in developing countries like India. And due to proven role of folate in various maternal and fetal anomalies, women are routinely prescribed folic acid under various national policies. However, B12 supplementation is rare, despite known deleterious effects of its deficiency. The purpose of this paper is to understand RPL through anemia with special reference to folate and B12 imbalance. Design/methodology/approach Multiparous women with normal obstetric outcomes (n=135) and women with Idiopathic RPL (n=105) were recruited in the study. All women were non-pregnant and belonged to North Indian population. Hb, serum folate and B12 and plasma homocysteine were measured in all the women. Anemia was classified according to WHO guidelines (Hemoglobin (Hb)<12g/dL). Findings The incidence of Anemia was more among normal multiparous women (73 percent) as compared to women with RPL (60 percent). However, unlike folate deficiency anemia among controls, B12 deficiency anemia was observed in women with RPL. Moreover, these women, despite being less anemic, with high B12 deficiency and folate sufficiency (presumably due to folate supplementation) had more imbalanced vitamin metabolism, as evident from homocysteine levels. The study suggests that anemic or non-anemic deficiencies of B12 and folate among women with RPL may be combated by screening for both vitamins, rather than supplementing folate indiscriminately to all. Research limitations/implications One of the limitations is that ferritin levels for iron deficiency anemia could not be measured in this study. Originality/value The present study is the first study, to the best of our knowledge, where we looked for the role of imbalance of folate and B12 in women with RPL.

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Section: Resultsmentioning

confidence: 99%

Recurrent pregnancy lossesvis-à-visanemia and vitamin (Folate/B12) imbalance

Kaur

Puri

Saraswathy

et al. 2018

IJHG

Self Cite

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“…Therefore, the genes whose m 6 A modification decreased while the expression increased became the main genes of interest and 14 genes among the 65 genes were selected in the hyper-down quadrant. Based on the gene function, we finally selected six genes (EMILIN1, MTR, LGI2, ZBTB4, TFAP4, and PLSCR3) which were closely related to cell proliferation, migration, and apoptosis ( Danussi et al, 2012 ; Khot et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

METTL3-Mediated m6A RNA Methylation of ZBTB4 Interferes With Trophoblast Invasion and Maybe Involved in RSA

Huang

Zhang

et al. 2022

Front. Cell Dev. Biol.

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N6-methyladenosine (m6A) was the most abundant modification of mRNA and lncRNA in mammalian cells and played an important role in many biological processes. However, whether m6A modification was associated with recurrent spontaneous abortion (RSA) and its roles were still unclear.Methods: Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) was used to study the global m6A modification pattern in RSAs and controls. RNA sequencing (RNA-Seq) was used to study the level of global mRNA in two groups. Real-time quantitative PCR (RT-qPCR) was used to verify the level of mRNA of METTL3 and ZBTB4. MeRIP–qPCR was conducted to test the level of ZBTB4 m6A modification in two groups. In order to further explore whether ZBTB4 was the substrate of METTL3, the HTR-8/SVneo (HTR-8) cell line was selected for the knockdown and overexpression of METTL3. To study whether METTL3 regulated the ZBTB4 expression by recognizing ZBTB4 mRNA m6A motifs in coding sequences (CDS), dual-luciferase reporter assay was conducted. RNA stability assays using actinomycin D were conducted to study the RNA stability of the HTR-8 cell line with METTL3 overexpression and knockdown. To illustrate the role of METTL3 in the invasion of trophoblast, matrigel invasion assays and transwell migration assays were conducted using the HTR-8 cell line with METTL3 overexpression and knockdown.Results: A total of 65 genes were found with significant differences both in m6A modification and mRNA expression. We found m6A methyltransferase METTL3 was significantly down-regulated in the RSA group. Through gene function analysis, RT-qPCR, MeRIP–qPCR validation experiment, knockdown, and overexpression of METTL3 in the HTR-8 cell line, ZBTB4 was selected as one target of METTL3. Furthermore, we clarified that METTL3 regulated the expression of ZBTB4 by recognizing ZBTB4 mRNA m6A motifs in the CDS using the dual-luciferase reporter assay and METTL3 regulated the invasion of trophoblast by altering the stability and expression of ZBTB4 by RNA stability, matrigel invasion, and transwell migration assays.Conclusion: Our study revealed the mechanism by which METTL3 regulated the stability and expression of ZBTB4 and the trophoblast migration ability of RSA. A new perspective was provided for exploring the mechanism of embryonic development in RSA patients.

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“…To maintain full-term pregnancy, it is important to have an adequate, controlled internal maternal environment for embryo's growth and development. DNA methylation has a critical role in cellular growth and differentiation of trophoblastic cell lines [15]. The MTHFR gene which is the topic of our study is one of the nonimprinted genes involved in pregnancy loss.…”

Section: Discussionmentioning

confidence: 97%

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

Sakai

Shalabi

Amr

2021

Journal of Genetic Engineering and Biotechnology

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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.

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Hypermethylated CpG Sites in the MTR Gene Promoter in Preterm Placenta

Abstract: Study suggests a dysregulation of enzyme genes in remethylation arm of the one-carbon metabolism in placenta of women delivering preterm.

Cited by 13 publications

References 51 publications

Recurrent pregnancy lossesvis-à-visanemia and vitamin (Folate/B12) imbalance

Recurrent pregnancy lossesvis-à-visanemia and vitamin (Folate/B12) imbalance

METTL3-Mediated m6A RNA Methylation of ZBTB4 Interferes With Trophoblast Invasion and Maybe Involved in RSA

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

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