Tissue-specific distribution of aberrant DNA methylation associated with maternal low-folate status in human neural tube defects

Chang, Huibo; Zhang, Ting; Zhang, Zhiping; Bao, Rui; Fu, Chengbo; Wang, Zhigang; Bao, Yihua; Li, Yuanyuan; Wu, Lihua; Zheng, Xiaoying; Wu, Jianxin

doi:10.1016/j.jnutbio.2010.10.003

Cited by 100 publications

(70 citation statements)

References 27 publications

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“…3 DNA methylation is a widely studied epigenetic modification, tightly regulated during hematopoietic development. 4,5 Studies show that environmental exposures, such as dietary factors 6,7 and air pollution, 8 as well as stochastic factors can alter DNA methylation profiles in blood. Thus, variation in the DNA methylation profile during immune development could stably alter the host immune response at the individual level, or may underscore much of the variation in the clinical manifestations of allergic diseases at the population level.…”

Section: Introductionmentioning

confidence: 99%

Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy

et al. 2014

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Section: Introductionmentioning

confidence: 99%

Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy

et al. 2014

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“…Disruption of the methyl cycle is known to induce NTDs in cultured mouse embryos (31) and cranial defects are observed in DNA methyltransferase 3b nullizygous embryos (32). Recent studies in humans have linked maternal folate status and occurrence of NTDs to tissue-specific DNA hypo-and hypermethylation patterns, with decreased DNA methylation observed in NTD brain tissue compared with normal embryos (33). Protein methylation is also involved in neural tube development, and hypomethylation of neural tube proteins is accompanied by a failure of the neural tube to close in rat embryos cultured in methionine-deficient conditions (34).…”

Section: Discussionmentioning

confidence: 99%

Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice

Momb¹,

Lewandowski

Bryant³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

138

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Maternal supplementation with folic acid is known to reduce the incidence of neural tube defects (NTDs) by as much as 70%. Despite the strong clinical link between folate and NTDs, the biochemical mechanisms through which folic acid acts during neural tube development remain undefined. The Mthfd1l gene encodes a mitochondrial monofunctional 10-formyl-tetrahydrofolate synthetase, termed MTHFD1L. This gene is expressed in adults and at all stages of mammalian embryogenesis with localized regions of higher expression along the neural tube, developing brain, craniofacial structures, limb buds, and tail bud. In both embryos and adults, MTHFD1L catalyzes the last step in the flow of one-carbon units from mitochondria to cytoplasm, producing formate from 10-formyl-THF. To investigate the role of mitochondrial formate production during embryonic development, we have analyzed Mthfd1l knockout mice. All embryos lacking Mthfd1l exhibit aberrant neural tube closure including craniorachischisis and exencephaly and/or a wavy neural tube. This fully penetrant folate-pathway mouse model does not require feeding a folate-deficient diet to cause this phenotype. Maternal supplementation with sodium formate decreases the incidence of NTDs and partially rescues the growth defect in embryos lacking Mthfd1l . These results reveal the critical role of mitochondrially derived formate in mammalian development, providing a mechanistic link between folic acid and NTDs. In light of previous studies linking a common splice variant in the human MTHFD1L gene with increased risk for NTDs, this mouse model provides a powerful system to help elucidate the specific metabolic mechanisms that underlie folate-associated birth defects, including NTDs.

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“…Findings of global DNA and LINE-1 hypomethylation were found in fetal neural tissue DNA from NTD patients, suggesting that disruption of genomic stability may lead to abnormal neural tube closure. 11,12 The methylation hypothesis suggests that folic acid prevents NTDs by enhancing cellular methylation reactions. It is known that a tight regulation of genome-wide erasure of epigenetic footprints with resetting of the methylation signature is critical for normal embryogenesis and, therefore, it is believed that DNA methylation changes and genomic instability may disturb neural tube folding.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation analysis of Homeobox genes implicatesHOXB7hypomethylation as risk factor for neural tube defects

et al. 2015

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Tissue-specific distribution of aberrant DNA methylation associated with maternal low-folate status in human neural tube defects

Cited by 100 publications

References 27 publications

Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy

Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy

Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice

DNA methylation analysis of Homeobox genes implicatesHOXB7hypomethylation as risk factor for neural tube defects

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