Inhibition of methylation and changes in gene expression in relation to neural tube defects

Linden, Ivon J. M. van der; Heil, Sandra G.; Petersen, Michael van Egmont; Straaten, Henny W. van; Heijer, Martin den; Blom, Henk J.

doi:10.1002/bdra.20509

Cited by 23 publications

(13 citation statements)

References 38 publications

(46 reference statements)

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“…Among the local autism mothers, the G allele load was positively correlated with lymphocyte DNA hypomethylation (Table VII and Figure 3). In both animal and human studies, DNA hypomethylation has been negatively correlated with folate status and positively correlated with homocysteine and SAH (van der Linden et al 2008;Chen et al 2001;Niculescu and Zeisel 2002;Jacob et al 1998;Yi et al 2000). Maternal folate insufficiency can stem from genetic aberrations, nutritional deficiencies, and/or environmental exposures that increase folate requirement for DNA synthesis and DNA methylation during fetal development.…”

Section: Discussionmentioning

confidence: 99%

A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism

James

Melnyk

Jernigan

et al. 2010

American J of Med Genetics Pt B

109

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The biologic basis of autism is complex and is thought to involve multiple and variable gene-environment interactions. While the logical focus has been on the affected child, the impact of maternal genetics on intrauterine microenvironment during pivotal developmental windows could be substantial. Folate-dependent one carbon metabolism is a highly polymorphic pathway that regulates the distribution of one-carbon derivatives between DNA synthesis (proliferation) and DNA methylation (cell-specific gene expression and differentiation). These pathways are essential to support the programmed shifts between proliferation and differentiation during embryogenesis and organogenesis. Maternal genetic variants that compromise intrauterine availability of folate derivatives could alter fetal cell trajectories and disrupt normal neurodevelopment. In this investigation, the frequency of common functional polymorphisms in the folate pathway was investigated in a large population-based sample of autism case-parent triads. In case-control analysis, a significant increase in the reduced folate carrier (RFC1) G allele frequency was found among case mothers, but not among fathers or affected children. Subsequent log linear analysis of the RFC1 A80G genotype within family trios revealed that the maternal G allele was associated with a significant increase in risk of autism whereas the inherited genotype of the child was not. Further, maternal DNA from the autism mothers was found to be significantly hypomethylated relative to reference control DNA. Metabolic profiling indicated that plasma homocysteine, adenosine, and S-adenosylhomocyteine were significantly elevated among autism mothers consistent with reduced methylation capacity and DNA hypomethylation. Together, these results suggest that the maternal genetics/epigenetics may influence fetal predisposition to autism.

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Section: Discussionmentioning

confidence: 99%

A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism

James

Melnyk

Jernigan

et al. 2010

American J of Med Genetics Pt B

109

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“…Homozygous null embryos for DNMT3B70 , coding for one of the enzymes for DNA methylation is responsible for cranial NTDs [150]. Dysregulation of gene expression has also been observed in chick embryos, treated with methylation inhibitors leading to a widening of the anterior neuropore [151]. On the other hand, NTDs are not observed in null embryos for MTHFR , despite a significant reduction in the methylation ratio and global DNA methylation [152].…”

Section: Putative Mechanisms Of Folates Actionmentioning

confidence: 99%

Neural Tube Defects, Folic Acid and Methylation

Imbard

Benoist

Blom

2013

IJERPH

225

164

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Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects.

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“…Another study demonstrated that global DNA hypomethylation is associated with NTD‐affected pregnancy (Christman et al, 1993). Several reports have shown that methylation cycle inhibition induces a high frequency of cranial NTDs in cultured mouse and chick embryos (Dunlevy et al, 2006; Van der Linden et al, 2008). Thus, impaired genomic methylation may underlie the complex pathogenesis of NTDs.…”

Section: Introductionmentioning

confidence: 99%

“…Several reports have shown that methylation cycle inhibition induces a high frequency of cranial NTDs in cultured mouse and 0736-5748/$36.00 © 2011 Published by Elsevier Ltd on behalf of ISDN. doi:10.1016/j.ijdevneu.2011.06.006 chick embryos (Dunlevy et al, 2006;Van der Linden et al, 2008). Thus, impaired genomic methylation may underlie the complex pathogenesis of NTDs.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress is implicated in arsenic‐induced neural tube defects in chick embryos

Han

Song

Cui

et al. 2011

Intl J of Devlp Neuroscience

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The potential of arsenic to induce neural tube defects (NTDs) remains a topic of controversy. In our previous study, oxidative stress and altered DNA methylation were observed in arsenic-exposed animal models. However, the correlation between these conditions was not fully understood. Therefore, our present aim was to determine whether arsenic exposure results in altered reactive oxygen species levels that affect DNA methylation and may contribute to NTDs in chick embryos. We demonstrated that arsenic-induced NTDs were associated with oxidative stress. Increased intracellular oxidative species and DNA methylation changes were observed following arsenic exposure. These changes were accompanied by a decrease in manganese superoxide dismutase activity. Furthermore, a significant decrease in DNA methyltransferase (DNMT) 1 and 3a expression was observed following arsenic exposure. The known antioxidant N-acetyl-l-cysteine, a known antioxidant, ameliorated global DNA hypomethylation and the decreased DNMT 1 and 3a expression observed during arsenic exposure. In addition, arsenic caused a significant decrease in S-adenosylmethionine (SAM) and significant increase in S-adenosylhomocysteine (SAH). This effect resulted in a significant reduction of the SAM/SAH ratio, which may also contribute to DNA hypomethylation. In conclusion, oxidative stress and reduction in SAM/SAH ratio during arsenic exposure in chick embryos seem to modulate DNA methylation and contribute to arsenic-induced NTDs via epigenetic mechanisms.

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Inhibition of methylation and changes in gene expression in relation to neural tube defects

Abstract: Inhibition of methylation by Adox affects gene expression in our in vitro chick embryo model. Further research will focus on the gene-specific methylation patterns of PSPH, ULK1, and CXCL12/SDF-1 and the role of the products of these genes in neurulation.

Cited by 23 publications

References 38 publications

A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism

A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism

Neural Tube Defects, Folic Acid and Methylation

Oxidative stress is implicated in arsenic‐induced neural tube defects in chick embryos

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