DNA methylation aberrations rather than polymorphisms of <i>FZD3</i> gene increase the risk of spina bifida in a high‐risk region for neural tube defects

Shangguan, Shaofang; Wang, Li; Chang, Shaoyan; Lü, Xiaoling; Wang, Zhen; Wu, Lihua; Wang, Jianhua; Wang, Xiuwei; Guan, Zhiyong; Bao, Yihua; Zhao, Hengyu; Zou, Jizhen; Niu, Bo; Zhang, Ting

doi:10.1002/bdra.23285

Cited by 12 publications

(10 citation statements)

References 26 publications

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“…35 Aberrant methylation of the FZD3 gene, a PCP component, was observed in brain tissue in human spina bifida and showed an association with human NTD development. 12 Our findings expand the knowledge of the relation between these pathways and NTD development.…”

Section: Discussionsupporting

confidence: 67%

“…Besides vague effect of global DNA methylation, disruption of methylation at specific genes has been linked to NTDs, such as imprinted genes, 9,10 transposon genes, 7 DNA repair genes, 11 planar-cell polarity genes, 12 folate receptor genes, 13 and HOX genes. 14 Hypermethylation or hypomethylation of these specific genes was identified in NTD cases by targeted gene methylation profiling.…”

Section: Introductionmentioning

confidence: 99%

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Fetal DNA hypermethylation in tight junction pathway is associated with neural tube defects: A genome-wide DNA methylation analysis

et al. 2017

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Neural tube defects (NTDs) are a spectrum of severe congenital malformations of fusion failure of the neural tube during early embryogenesis. Evidence on aberrant DNA methylation in NTD development remains scarce, especially when exposure to environmental pollutant is taken into consideration. DNA methylation profiling was quantified using the Infinium HumanMethylation450 array in neural tissues from 10 NTD cases and 8 non-malformed controls (stage 1). Subsequent validation was performed using a Sequenom MassARRAY system in neural tissues from 20 NTD cases and 20 non-malformed controls (stage 2). Correlation analysis of differentially methylated CpG sites in fetal neural tissues and polycyclic aromatic hydrocarbons concentrations in fetal neural tissues and maternal serum was conducted. Differentially methylated CpG sites of neural tissues were further validated in fetal mice with NTDs induced by benzo(a)pyrene given to pregnant mice. Differentially hypermethylated CpG sites in neural tissues from 17 genes and 6 pathways were identified in stage 1. Subsequently, differentially hypermethylated CpG sites in neural tissues from 6 genes (BDKRB2, CTNNA1, CYFIP2, MMP7, MYH2, and TIAM2) were confirmed in stage 2. Correlation analysis showed that methylated CpG sites in CTNNA1 and MYH2 from NTD cases were positively correlated to polycyclic aromatic hydrocarbon level in fetal neural tissues and maternal serum. The correlation was confirmed in NTD-affected fetal mice that were exposed to benzo(a)pyrene in utero. In conclusion, hypermethylation of the CTNNA1 and MYH2 genes in tight junction pathway is associated with the risk for NTDs, and the DNA methylation aberration may be caused by exposure to benzo(a)pyrene.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Fetal DNA hypermethylation in tight junction pathway is associated with neural tube defects: A genome-wide DNA methylation analysis

et al. 2017

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“…Recent studies have demonstrated that global DNA hypomethylation, evaluated using LINE-1 methylation as an indicator in human fetuses, was associated with an increased risk for NTDs [9]. Aberrations of methylation at specific genes are reported to be involved in NTDs, including imprinted genes [10, 11], DNA repair genes [12], planar-cell polarity genes [13, 14], and HOX genes [15].…”

Section: Introductionmentioning

confidence: 99%

Aberrant methylation of Pax3 gene and neural tube defects in association with exposure to polycyclic aromatic hydrocarbons

Lin

Ren²,

Wang³

et al. 2019

Clin Epigenet

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BackgroundNeural tube defects (NTDs) are common and severe congenital malformations. Pax3 is an essential gene for neural tube closure in mice but it is unknown whether altered expression or methylation of PAX3 contributes to human NTDs. We examined the potential role of hypermethylation of Pax3 in the development of NTDs by analyzing human NTD cases and a mouse model in which NTDs were induced by benzo[a]pyrene (BaP), a widely studied polycyclic aromatic hydrocarbon (PAH).MethodsWe extracted methylation information of PAX3 in neural tissues from array data of ten NTD cases and eight non-malformed controls. A validation study was then performed in a larger independent population comprising 73 NTD cases and 29 controls. Finally, we examined methylation patterns and expression of Pax3 in neural tissues from mouse embryos of dams exposed to BaP or BaP and vitamin E.ResultsSeven CpG sites in PAX3 were hypermethylated in NTD fetuses as compared to controls in the array data. In the validation phase, significantly higher methylation levels in the body region of PAX3 were observed in NTD cases than in controls (P = 0.003). And mean methylation intensity in the body region of PAX3 in fetal neural tissues was positively correlated with median concentrations of PAH in maternal serum. In the mouse model, BaP-induced NTDs were associated with hypermethylation of specific CpG sites within both the promoter and body region of Pax3. Supplementation with vitamin E via chow decreased the rate of NTDs, partly recovered the repressed total antioxidant capacity in mouse embryos exposed to BaP, and this was accompanied by the normalization of Pax3 methylation level and gene expression.ConclusionHypermethylation of Pax3 may play a role in the development of NTDs; DNA methylation aberration may be caused by exposure to BaP, with possible involvement of oxidative stress.Electronic supplementary materialThe online version of this article (10.1186/s13148-019-0611-7) contains supplementary material, which is available to authorized users.

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“…Research from countries without FA fortification also lends support to the methylation hypothesis. A slight reduction in genome-wide DNAm was noted in NTD cases in China [ 14 – 16 ], in addition to changes in NTD DNAm at specific genes relevant to fetal development in China, Belgium, and the Netherlands: imprinted [ 17 ], planar-cell polarity [ 18 , 19 ], HOX [ 20 ], and folate receptor genes [ 21 ]. Some of the findings are, however, undermined by small magnitude of change in DNAm, a lack of statistical correction for multiple comparisons, and use of peripheral tissues.…”

Section: Introductionmentioning

confidence: 99%

Profiling placental and fetal DNA methylation in human neural tube defects

Price

Peñaherrera

Portales-Casamar

et al. 2016

Epigenetics & Chromatin

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BackgroundThe incidence of neural tube defects (NTDs) declined by about 40 % in Canada with the introduction of a national folic acid (FA) fortification program. Despite the fact that few Canadians currently exhibit folate deficiency, NTDs are still the second most common congenital abnormality. FA fortification may have aided in reducing the incidence of NTDs by overcoming abnormal one carbon metabolism cycling, the process which provides one carbon units for methylation of DNA. We considered that NTDs persisting in a folate-replete population may also occur in the context of FA-independent compromised one carbon metabolism, and that this might manifest as abnormal DNA methylation (DNAm). Second trimester human placental chorionic villi, kidney, spinal cord, brain, and muscle were collected from 19 control, 22 spina bifida, and 15 anencephalic fetuses in British Columbia, Canada. DNA was extracted, assessed for methylenetetrahydrofolate reductase (MTHFR) genotype and for genome-wide DNAm using repetitive elements, in addition to the Illumina Infinium HumanMethylation450 (450k) array.ResultsNo difference in repetitive element DNAm was noted between NTD status groups. Using a false discovery rate <0.05 and average group difference in DNAm ≥0.05, differentially methylated array sites were identified only in (1) the comparison of anencephaly to controls in chorionic villi (n = 4 sites) and (2) the comparison of spina bifida to controls in kidney (n = 3342 sites).ConclusionsWe suggest that the distinctive DNAm of spina bifida kidneys may be consequent to the neural tube defect or reflective of a common etiology for abnormal neural tube and renal development. Though there were some small shifts in DNAm in the other tested tissues, our data do not support the long-standing hypothesis of generalized altered genome-wide DNAm in NTDs. This finding may be related to the fact that most Canadians are not folate deficient, but it importantly opens the field to the investigation of other epigenetic and non-epigenetic mechanisms in the etiology of NTDs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0054-8) contains supplementary material, which is available to authorized users.

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DNA methylation aberrations rather than polymorphisms of FZD3 gene increase the risk of spina bifida in a high‐risk region for neural tube defects

Abstract: The results of this study suggest that DNA methylation plays an important role in FZD3 gene expression regulation and may be associated with an increased risk of spina bifida.

Cited by 12 publications

References 26 publications

Fetal DNA hypermethylation in tight junction pathway is associated with neural tube defects: A genome-wide DNA methylation analysis

Fetal DNA hypermethylation in tight junction pathway is associated with neural tube defects: A genome-wide DNA methylation analysis

Aberrant methylation of Pax3 gene and neural tube defects in association with exposure to polycyclic aromatic hydrocarbons

Profiling placental and fetal DNA methylation in human neural tube defects

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