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Altered methylation of IGF2 DMR0 is associated with neural tube defects

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Abstract

Neural tube defects (NTDs) are serious congenital malformation of fusion failure of the neural tube during early embryogenesis. DNA methylation disorders have been found in NTD-affected fetuses, and are correlated to the risk of NTDs. The insulin-like growth factor 2 (IGF2) gene, maternally imprinted, has a key role in fetal development. IGF2 transcription is partly controlled by differentially methylated regions (DMRs) 0 and 2. To assess whether disturbed methylation pattern increases the incidence of NTDs, we employed matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) to quantify CpG methylation levels of DMR2 and 0 in fetuses with or without NTDs. We found that the methylation level of IGF2 DMR0 increased significantly in the brain tissues of NTD-affected fetuses. And hypermethylation of DMR0 was associated with an increased risk of NTDs, with an odds ratio of 5.375 (95 % CI: 1.447–19.965; p = 0.007). IGF2 mRNA expression was negatively correlated with the methylation level of DMR0 (R 2 = 0.893; p = 0.000) in HCT15 cells. These results highlights that IGF2 DMR0 hypermethylation is a potential risk factor of NTD, and IGF2 gene is a promising candidate gene to study for a greater understanding of the cause of NTDs.

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Abbreviations

NTDs:

Neural tube defects

IGF2 :

Insulin-like growth factor 2

DMRs:

Differentially methylated regions

MALDI-TOF MS:

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

LINE-1:

Long interspersed nucleotide element 1

MGMT :

O6-methylguanine-DNA methyltransferase

IGF1R:

Insulin-like growth factor 1 receptor

ICR:

Imprinting control region

PCR:

Real-time polymerase chain reaction

5-Aza-CdR:

5-Aza-2′-deoxycytidine

ANOVA:

One-way analysis of variance

ORs:

Odds ratios

CIs:

Confidence intervals

AORs:

Adjusted odds ratios

SRS:

Silver–Russell syndrome

Shh:

Sonic hedgehog

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Acknowledgments

We are grateful to all participating hospitals and medical staff for their implementation in sample collections and clinical information recordings, and we thank all of the women who participated, for their cooperation. This study was supported by the special research projects of health industry “infant malnutrition assessment and intervention (201002006)”, the National Natural Science Fund of China (81000249 and 81150008), the Young Scientists Research Fund of Beijing Municipal Health Bureau (2010–2012).

Conflict of interest

None of the authors has a conflict of interest to declare.

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Authors and Affiliations

  1. Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, No. 2, Yabao Road, Chao Yang District, Beijing, 100020, People’s Republic of China

    Lihua Wu, Li Wang, Shaofang Shangguan, Shaoyan Chang, Zhen Wang, Xiaolin Lu, Qin Zhang, Jianhua Wang, Huizhi Zhao, Fang Wang, Jin Guo, Bo Niu & Ting Zhang

  2. Peking University People’s Hospital, No. 11 Xizhimen South Street, Xi Chen District, Beijing, 100044, People’s Republic of China

    Jingzhu Guo

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  1. Lihua Wu
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Correspondence to Jingzhu Guo or Ting Zhang.

Additional information

Lihua Wu and Li Wang contributed equally to this manuscript.

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11010_2013_1655_MOESM1_ESM.tif

Supplementary Fig. 1 Methylation level of DMR0 in HCT15 cells treated with various concentrations of 5-Aza-CdR. * p < 0.05 (TIFF 866 kb)

Supplementary material 2 (DOC 37 kb)

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Wu, L., Wang, L., Shangguan, S. et al. Altered methylation of IGF2 DMR0 is associated with neural tube defects. Mol Cell Biochem 380, 33–42 (2013). https://doi.org/10.1007/s11010-013-1655-1

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  • DOI: https://doi.org/10.1007/s11010-013-1655-1

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