Hypomethylation of GRHL3 gene is associated with the occurrence of neural tube defects

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Abstract

<div class="section"> <a class="named-anchor" id="d8963378e204">  </a> <h5 class="section-title" id="d8963378e205">Aim:</h5> <p id="d8963378e207">To investigate the relationship between <i>GRHL3</i> methylation and the etiology of neural tube defects (NTDs). </p> </div><div class="section"> <a class="named-anchor" id="d8963378e212">  </a> <h5 class="section-title" id="d8963378e213">Materials & methods:</h5> <p id="d8963378e215">Analyze data from a genome-wide DNA methylation array. Targeted DNA methylation analysis was performed for 46 cases and 23 controls. At last, <i>grhl3</i> overexpression and gene depletion experiments were conducted in zebrafish. </p> </div><div class="section"> <a class="named-anchor" id="d8963378e220">  </a> <h5 class="section-title" id="d8963378e221">Results:</h5> <p id="d8963378e223">Five hypomethylated CpGs were discovered in the methylation arrays performed on NTD cases. In a validation study, 15 hypomethylated CpGs were found and the overall methylation levels decreased in brain/spinal cord tissue from NTD cases. The knockdown and overexpression of <i>grhl3</i> in zebrafish damaged embryonic convergent extension processes. </p> </div><div class="section"> <a class="named-anchor" id="d8963378e228">  </a> <h5 class="section-title" id="d8963378e229">Conclusion:</h5> <p id="d8963378e231">Hypomethylation of <i>GRHL3</i> in central nervous tissue is associated with NTDs, further supporting the importance of <i>GRHL3</i> and methylation in proper neural tube closure. </p> </div>

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Comprehensive analysis of CpG islands in human chromosomes 21 and 22.

Daiya Takai, Peter A. Jones (2002)

CpG islands are useful markers for genes in organisms containing 5-methylcytosine in their genomes. In addition, CpG islands located in the promoter regions of genes can play important roles in gene silencing during processes such as X-chromosome inactivation, imprinting, and silencing of intragenomic parasites. The generally accepted definition of what constitutes a CpG island was proposed in 1987 by Gardiner-Garden and Frommer [Gardiner-Garden, M. & Frommer, M. (1987) J. Mol. Biol. 196, 261-282] as being a 200-bp stretch of DNA with a C+G content of 50% and an observed CpG/expected CpG in excess of 0.6. Any definition of a CpG island is somewhat arbitrary, and this one, which was derived before the sequencing of mammalian genomes, will include many sequences that are not necessarily associated with controlling regions of genes but rather are associated with intragenomic parasites. We have therefore used the complete genomic sequences of human chromosomes 21 and 22 to examine the properties of CpG islands in different sequence classes by using a search algorithm that we have developed. Regions of DNA of greater than 500 bp with a G+C equal to or greater than 55% and observed CpG/expected CpG of 0.65 were more likely to be associated with the 5' regions of genes and this definition excluded most Alu-repetitive elements. We also used genome sequences to show strong CpG suppression in the human genome and slight suppression in Drosophila melanogaster and Saccharomyces cerevisiae. This finding is compatible with the recent detection of 5-methylcytosine in Drosophila, and might suggest that S. cerevisiae has, or once had, CpG methylation.

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A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status.

Simonetta Friso, Sang-Woon Choi, Domenico Girelli … (2002)

DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-l-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-l-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T/T) and 187 homozygous for the wild-type (C/C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T/T genotypes had a diminished level of DNA methylation compared with those with the C/C wild-type (32.23 vs.62.24 ng 5-methylcytosine/microg DNA, P < 0.0001). When analyzed according to folate status, however, only the T/T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T/T subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status.

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An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure.

Rachel Harris, Diana M Juriloff (2010)

The number of mouse mutants and strains with neural tube defects (NTDs) now exceeds 240, including 205 representing specific genes, 30 for unidentified genes, and 9 multifactorial strains. These mutants identify genes needed for embryonic neural tube closure. Reports of 50 new NTD mutants since our 2007 review (Harris and Juriloff, 2007) were considered in relation to the previously reviewed mutants to obtain new insights into mechanisms of NTD etiology. In addition to null mutations, some are hypomorphs or conditional mutants. Some mutations do not cause NTDs on their own, but do so in digenic, trigenic, and oligogenic combinations, an etiology that likely parallels the nature of genetic etiology of human NTDs. Mutants that have only exencephaly are fourfold more frequent than those that have spina bifida aperta with or without exencephaly. Many diverse cellular functions and biochemical pathways are involved; the NTD mutants draw new attention to chromatin modification (epigenetics), the protease-activated receptor cascade, and the ciliopathies. Few mutants directly involve folate metabolism. Prevention of NTDs by maternal folate supplementation has been tested in 13 mutants and reduces NTD frequency in six diverse mutants. Inositol reduces spina bifida aperta frequency in the curly tail mutant, and three new mutants involve inositol metabolism. The many NTD mutants are the foundation for a future complete genetic understanding of the processes of neural fold elevation and fusion along mechanistically distinct cranial-caudal segments of the neural tube, and they point to several candidate processes for study in human NTD etiology.

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Author and article information

Journal

Title: Epigenomics

Abbreviated Title: Epigenomics

Publisher: Future Medicine Ltd

ISSN (Print): 1750-1911

ISSN (Electronic): 1750-192X

Publication date Created: July 2018

Publication date (Print): July 2018

Volume: 10

Issue: 7

Pages: 891-901

Affiliations

[1 ]Institute of Reproductive & Child Health, Ministry of Health Key Laboratory of Reproductive Health, Department of Epidemiology & Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, PR China

[2 ]Key Laboratory of Cell Proliferation & Differentiation of Ministry of Education, College of Life Sciences, Peking University, Beijing, PR China

[3 ]Departments of Molecular & Cellular Biology & Medicine, Baylor College of Medicine, Houston, TX 77030, USA

Article

DOI: 10.2217/epi-2018-0016

PMC ID: 6077761

PubMed ID: 29587534

SO-VID: 82eaed99-d187-4506-895d-9643f1d86ab6

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Hypomethylation of GRHL3 gene is associated with the occurrence of neural tube defects

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CRISPR/Cas9 editing in human blood

Most cited references 23

Comprehensive analysis of CpG islands in human chromosomes 21 and 22.

A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status.

An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure.

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