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ABSTRACT: Neural tube defects (NTDs) are severe, common birth defects that result from failure of neural tube closure, but their pathological mechanisms are not yet fully understood. Histone modifications have an important role in gene regulation during fetal development. We therefore hypothesized that the human NTDs may be partly caused by an imbalance in metabolism, perhaps caused by nutritional deficiencies, that leads to aberrant histone modifications. Here, we report a screen of fetal brain histone modifications using 2D nano-LC strong cation exchange reverse phase (SCX/RP) MS/MS and the identification of 61 unique post-translational modification sites on histones H1, H2a, H2b, H3, and H4. Of these, 38 sites are novel (not already found in the Uniprot database). Furthermore, we compared the histone modification patterns between normal brains and NTD brains special of which maternal folate levels were lower than of normal control. The results showed that histone H3 lysine 79 dimethylation (H3K79me2) and a novel identified site, H2bK5 monomethylation (H2bK5me1), were completely absent in individuals with NTDs. Follow-up western blotting validated the decreased H3K79me2 expression in brains with NTDs, but the amplified samples experiments displayed that decreased H3K79me2 expression was not suitable for all samples with NTDs. Furthermore, folate-free treated mouse embryonic stem cells induced the decreased H3K79me2 level. Subsequently, our ChIP results in normal fetal brain tissues showed that H3K79me2 binds to SUFU, RARA and ITGA3 which induce NTDs phenotype after knockout in mice, and in NTDs brain tissues the bindings of H3K79me2 to these three genes were significantly altered. Taken together, our study indicated that low folate treatment might attenuate H3K79 dimethylation, further affect its regulate activation on target genes, some of which are NTDs-resulting associated, lastly interrupt early embryo developing. Our study increases the understanding of normal fetal brain histone modifications and provides a platform for investigating histone modifications in neural disease and also has an insight into a potential role of aberrant histone modification in etiology of NTDs.
Neurobiology of Disease 01/2013; · 5.40 Impact Factor
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Xiaoli Chen,
Yiping Shen,
Yonghui Gao,
Huizhi Zhao,
Xiaoming Sheng,
Jizhen Zou,
Va Lip,
Hua Xie,
Jin Guo,
Hong Shao, Yihua Bao,
Jianliang Shen,
Bo Niu,
James F Gusella,
Bai-Lin Wu,
Ting Zhang
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ABSTRACT: Neural tube defects (NTDs) are one of the most common birth defects caused by a combination of genetic and environmental factors. Currently, little is known about the genetic basis of NTDs although up to 70% of human NTDs were reported to be attributed to genetic factors. Here we performed genome-wide copy number variants (CNVs) detection in a cohort of Chinese NTD patients in order to exam the potential role of CNVs in the pathogenesis of NTDs.
The genomic DNA from eighty-five NTD cases and seventy-five matched normal controls were subjected for whole genome CNVs analysis. Non-DGV (the Database of Genomic Variants) CNVs from each group were further analyzed for their associations with NTDs. Gene content in non-DGV CNVs as well as participating pathways were examined.
Fifty-five and twenty-six non-DGV CNVs were detected in cases and controls respectively. Among them, forty and nineteen CNVs involve genes (genic CNV). Significantly more non-DGV CNVs and non-DGV genic CNVs were detected in NTD patients than in control (41.2% vs. 25.3%, p<0.05 and 37.6% vs. 20%, p<0.05). Non-DGV genic CNVs are associated with a 2.65-fold increased risk for NTDs (95% CI: 1.24-5.87). Interestingly, there are 41 cilia genes involved in non-DGV CNVs from NTD patients which is significantly enriched in cases compared with that in controls (24.7% vs. 9.3%, p<0.05), corresponding with a 3.19-fold increased risk for NTDs (95% CI: 1.27-8.01). Pathway analyses further suggested that two ciliogenesis pathways, tight junction and protein kinase A signaling, are top canonical pathways implicated in NTD-specific CNVs, and these two novel pathways interact with known NTD pathways.
Evidence from the genome-wide CNV study suggests that genic CNVs, particularly ciliogenic CNVs are associated with NTDs and two ciliogenesis pathways, tight junction and protein kinase A signaling, are potential pathways involved in NTD pathogenesis.
PLoS ONE 01/2013; 8(1):e54492. · 4.09 Impact Factor
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Jin Guo,
Hua Xie,
Jianhua Wang,
Huizhi Zhao,
Fang Wang,
Chi Liu,
Li Wang,
Xiaolin Lu, Yihua Bao,
Jizhen Zou,
Guoliang Wang,
Bo Niu,
Ting Zhang
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ABSTRACT: Folate hydrolase 1 (FOLH1) gene encodes intestinal folate hydrolase, which regulates intestinal absorption of dietary folate. Previous studies on the association between polymorphisms rs202676 and rs61886492 and the risk of neural tube defects (NTDs) were inconclusive. A case-control study of women with NTD-affected pregnancies (n = 160) and controls (n = 320) was conducted in the Chinese population of Lvliang, a high-risk area for NTDs. We genotyped the polymorphic sites rs202676 and rs61886492 and assessed maternal plasma folate and total homocysteine (tHcy). Our results showed that in case group, plasma folate concentrations were 18 % lower compared with those of control group (8.32 vs. 6.79 nmol/L, p = 0.033) and tHcy concentrations were 17 % higher (10.47 vs. 12.65 μmol/L, p = 0.047). Almost all samples had the rs61886492 GG genotype (99.78 %). The result showed that the frequency of GG genotype in rs202676 was significantly higher in group with multiple NTDs than in controls (p = 0.030, OR = 2.157, 95 % CI, 1.06-4.38). The multiple-NTD group showed higher maternal plasma concentrations of tHcy (10.47 vs. 13.96 μmol/L, p = 0.024). The GG genotype of rs202676 had a lower maternal folate and higher tHcy concentrations than other genotypes with no significant differences. The result of structural prediction indicated that this variation might change the spatial structure of the protein. These results suggested that the maternal polymorphism rs202676 was a potential risk factor for multiple NTDs in this Chinese population. The allele G might affect maternal plasma folate and tHcy concentration.
Genes & Nutrition 08/2012; · 2.51 Impact Factor
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Huizhi Zhao,
Fang Wang,
Jianhua Wang,
Hua Xie,
Jin Guo,
Chi Liu,
Li Wang,
Xiaolin Lu, Yihua Bao,
Guoliang Wang,
Rugang Zhong,
Bo Niu,
Ting Zhang
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ABSTRACT: Protein-L-isoaspartate (D-aspartate) O-methyltransferase 1 (PCMT1) gene encodes for the protein repair enzyme L-isoaspartate (D-aspartate) O-methyltransferase (PIMT), which is known to protect certain neural cells from Bax-induced apoptosis. Previous study has shown that PCMT1 polymorphisms rs4552 and rs4816 of infant are associated with spina bifida in the Californian population. The association between maternal polymorphism and neural tube defects is still uncovered. A case-control study was conducted to investigate a possible association between maternal PCMT1 and NTDs in Lvliang high-risk area of Shanxi Province in China, using a high-resolution DNA melting analysis genotyping method. We found that increased risk for anencephaly in isolated NTDs compared with the normal control group was observed for the G (vs. A) allele (p=0.034, OR=1.896, 95% CI, 1.04-3.45) and genotypes GG+GA (p=0.025, OR=2.237, 95% CI, 1.09-4.57). Although the significance was lost after multiple comparison correction, the results implied that maternal polymorphisms in PCMT1 might be a potential genetic risk factor for isolated anencephaly in this Chinese population.
Gene 05/2012; 505(2):340-4. · 2.34 Impact Factor
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ABSTRACT: Partitioning defective 3 homolog (PARD3) is an attractive candidate gene for screening neural tube defect (NTD) risk. To investigate the role of genetic variants in PARD3 on NTD risk, a case-control study was performed in a region of China with a high prevalence of NTDs. Total 53 single-nucleotide polymorphisms (SNPs) in PARD3 were genotyped in 224 fetuses with NTDs and in 253 normal fetuses. We found that 6 SNPs (rs2496720, rs2252655, rs3851068, rs118153230, rs10827337, and rs12218196) were statistically associated with NTDs (P < .05). After stratifying participants by NTD phenotypes, the significant association only existed in cases with anencephaly rather than spina bifida. Further haplotype analysis confirmed the association between PARD3 polymorphisms and NTD risk (global test P = 3.41e-008). Our results suggested that genetic variants in PARD3 were associated with susceptibility to NTDs in a Chinese Han population, and this association was affected by NTD phenotypes.
Reproductive sciences (Thousand Oaks, Calif.) 03/2012; 19(7):764-71. · 2.31 Impact Factor
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Hua Xie,
Jin Guo,
Jianhua Wang,
Fang Wang,
Huizhi Zhao,
Chi Liu,
Li Wang,
Xiaolin Lu,
Lihua Wu, Yihua Bao,
Jizhen Zou,
Ting Zhang,
Bo Niu
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ABSTRACT: Glutamate carboxypeptidase II (GCPII) catalyzes the hydrolysis of N-acetylaspartylglutamate into N-acetylaspartate and glutamate in the brain. Animal experiments suggested that GCPII plays an essential role in early embryonic development. Previous studies provided conflicting results on the effect of the GCPII rs61886492 C>T (or 1561C>T) polymorphism on NTDs. In the Lvliang area of Shanxi province, where the incidence of NTDs is the highest in China, a case-control study was conducted to investigate possible association between the GCPII rs61886492 and rs202676 polymorphisms and NTD risk. Results indicated all the case and control samples displayed the rs61886492 GG genotype. Although no significant differences in rs202676 genotype or allele frequencies were found between the NTD and control groups, the combined AG+GG genotype group was significantly associated with anencephaly (p = 0.03, OR = 2.11, 95% CI, 1.11-4.01), but not with spina bifida or encephalocele. Overall, the rs202676 A>G polymorphism is a potential risk factor for anencephaly. The results of this study suggest that phenotypic heterogeneity may exist among NTDs in this Chinese population.
Metabolic Brain Disease 11/2011; 27(1):59-65. · 2.20 Impact Factor
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Susanna Tran,
Li Wang,
Jing Le,
Jing Guan,
Lihua Wu,
Jizhen Zou,
Zhen Wang,
Jianhua Wang,
Fang Wang,
Xiaoli Chen,
Lingling Cai,
Xiaolin Lu,
Huizhi Zhao,
Jin Guo, Yihua Bao,
Xiaoying Zheng,
Ting Zhang
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ABSTRACT: DNA repair is critical for proper embryogenesis, and altered expression of DNA repair genes has been associated with neural tube defects (NTDs). The expression of DNA repair enzymes may be controlled, in part, by methylation of the promoter region. To assess whether disturbed promoter methylation pattern increases the incidence of NTDs, we employed methylation specific-multiplex ligation-dependent probe amplification (MS-MLPA) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) to quantify the methylation levels of multiple promoter CpG sites in normal human embryos and embryos with NTDs. Of the total seven DNA repair genes, two genes (MGMT, MSH6) were examined as having disturbed methylation levels by MS-MLPA kit, while only one gene was confirmed with a significant alternated methylation pattern by MALDI-TOF MS. In our research, methylation profiling of the DNA repair gene O (6)-methylguanine-DNA methyltransferase (MGMT) showed gender difference in embryogenesis. Comparison of MGMT promoter methylation revealed that hypomethylation was associated with an increased risk for cephalic malformations, especially with female embryos (Adjusted Odds Ratio = 8.250). The majority of individual CpG units within the promoter demonstrated hypomethylation. Meanwhile, the expression of MGMT was proven to increase significant in female cases. These results underscore the role of stable promoter methylation in the DNA repair enzymes MGMT for proper embryogenesis.
Journal of Molecular Neuroscience 11/2011; 47(1):42-51. · 2.50 Impact Factor
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Xiaoying Zheng,
Mingming Su,
Lijun Pei,
Ting Zhang,
Xu Ma,
Yunping Qiu,
Hongfei Xia,
Fang Wang,
Xiaojiao Zheng,
Xue Gu,
Xinming Song,
Xin Li,
Xin Qi,
Gong Chen, Yihua Bao,
Tianlu Chen,
Yi Chi,
Aihua Zhao,
Wei Jia
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ABSTRACT: Neural tube defects (NTDs) are one of the most common types of birth defects, affecting approximately 1 of every 1000 pregnancies in the United States and an estimated 300 000 newborns worldwide each year. The metabolic signature of pregnant women with NTDs in offspring has not previously been characterized. In this paper, we report a profiling study that characterized the serum metabolome of 101 pregnant women affected with NTDs in offspring in comparison with 143 pregnant women with normal pregnancy outcomes in Lvliang prefecture, the area with the highest birth prevalence of NTDs in China. A serum metabonomic study was also conducted to identify significantly altered metabolites associated with di-n-butyl phthalate (DBP)-induced teratogenesis in mice. The metabolic signature of NTD in pregnant women is characterized by the impaired mitochondrial respiration, neurotransmitter γ-aminobutyric acid, and methionine cycle. Of interest, consistent findings from DBP-induced teratogenesis in mice demonstrated increased succinate and decreased fumarate, suggesting an inhibited succinic dehydrogenase implicated in the defective mitochondria. The characteristic disruption of maternal metabolism offers important insights into metabolic mechanisms underlying human NTDs as well as potential preventive strategies.
Journal of Proteome Research 09/2011; 10(10):4845-54. · 5.11 Impact Factor
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Yiping Shen,
Xiaoli Chen,
Liwen Wang,
Jin Guo,
Jianliang Shen,
Yu An,
Haitao Zhu,
Yanli Zhu,
Ruolei Xin, Yihua Bao,
James F Gusella,
Ting Zhang,
Bai-Lin Wu
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ABSTRACT: The 16p11.2 deletion is a recurrent genomic event and a significant risk factor for autism spectrum disorders (ASD). This genomic disorder also exhibits extensive phenotypic variability and diverse clinical phenotypes. The full extent of phenotypic heterogeneity associated with the 16p11.2 deletion disorder and the factors that modify the clinical phenotypes are currently unknown. Multiplex families with deletion offer unique opportunities for exploring the degree of heterogeneity and implicating modifiers. Here we reported the clinical and genomic characteristics of three 16p11.2 deletion carriers in a Chinese family. The father carries a de novo 16p11.2 deletion, and it was transmitted to the proband and sib. The proband presented with ASD, intellectual disability, learning difficulty, congenital malformations such as atrial septal defect, scoliosis. His dysmorphic features included myopia and strabismus, flat and broad nasal bridge, etc. While the father shared same neurodevelopmental problems as the proband, the younger brother did not show many of the proband's phenotypes. The possible unmasked mutation of TBX6 and MVP gene in this deleted region and the differential distribution of other genomic CNVs were explored to explain the phenotypic heterogeneity in these carriers. This report demonstrated the different developmental trajectory and discordant phenotypes among family members with the same 16p11.2 deletion, thus further illustrated the phenotypic complexity and heterogeneity of the 16p11.2 deletion.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2011; 156(2):225-32. · 3.70 Impact Factor
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Huibo Chang,
Ting Zhang,
Zhiping Zhang,
Rui Bao,
Chengbo Fu,
Zhigang Wang, Yihua Bao,
Yuanyuan Li,
Lihua Wu,
Xiaoying Zheng,
Jianxin Wu
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ABSTRACT: This study compares the density and tissue-specific distribution of 5-methyl cytosine (5mC) in genomic DNA from human fetuses with or without neural tube defects (NTD) and examines whether low maternal serum folate is a possible correlate and/or risk factor for NTD. The results demonstrate significant hypomethylation of brain genomic DNA in NTD fetuses relative to controls (P<.01), as well as relative hypermethylation of skin and heart in NTD fetuses. In normal fetuses, the level of 5mC in liver genomic DNA decreased from fetal week 18 to 28 and increased over the same developmental period in kidney genomic DNA, but these trends were absent in genomic DNA from NTD fetuses. Mean maternal serum folate was significantly lower in NTD fetuses than in controls (P<.01), and maternal serum folate correlated with density of 5mC in genomic brain DNA from NTD fetuses (r=0.610). The results indicate that aberrant DNA methylation in NTD may be due to maternal folate deficiency and may be involved in the pathogenesis of NTD in humans.
The Journal of nutritional biochemistry 02/2011; 22(12):1172-7. · 4.29 Impact Factor
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Jianhua Wang,
Chi Liu,
Huizhi Zhao,
Fang Wang,
Jin Guo,
Hua Xie,
Xiaolin Lu, Yihua Bao,
Lijun Pei,
Bo Niu,
Rugang Zhong,
Xiaoying Zheng,
Ting Zhang
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ABSTRACT: Uncoupling protein 2(UCP2) is an attractive candidate gene for screening neural tube defects (NTDs) risk. In this study, polymerase chain reaction and agarose gel electrophoresis were used to determine the distribution of the polymorphism in a case group of 140 deliveries with NTDs, and a control group of 251 normal newborns. We found that the frequencies of allele I and genotypes ID + II were higher in the case group than in the control group (P = .167, OR = 1.4, 95% CI, 0.9-2.1; P = .132, OR = 1.44, 95% CI, 0.89-2.33, respectively); and at low maternal educational level, the frequency of ID + II genotypes was significantly higher in the NTD case group (P < .05, OR = 1.7, 95% CI, 1.01-2.79). The result suggested that the polymorphism in UCP2 may be a potential genetic risk factor for NTDs in a high-risk area of China, and the association was influenced by maternal education.
Reproductive sciences (Thousand Oaks, Calif.) 01/2011; 18(6):556-60. · 2.31 Impact Factor
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Xiaoli Chen,
Jin Guo,
Yunping Lei,
Jizhen Zou,
Xiaolin Lu, Yihua Bao,
Lihua Wu,
Jianxin Wu,
Xiaoying Zheng,
Yiping Shen,
Bai-Lin Wu,
Ting Zhang
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ABSTRACT: Neural tube defects are severe, common birth defects that result from failure of neural tube closure. They are considered to be a multifactorial disorder, and our knowledge of causal mechanisms remains limited. We hypothesized that abnormal DNA methylation occurs in NTD-affected fetuses. The correlations of global DNA methylation levels with complexity of NTDs and known risk factors of NTDs, MTHFR genotype and fever, were analyzed.
A hospital-based case-control study was performed. Epidemiologic data, pathologic diagnosis, and methylenetetrahydrofolate reductase (MTHFR) genotype analysis were completed. Array comparative genomic hybridization was used to exclude cytogenetic abnormalities. Global DNA methylation statuses were determined for both brain and skin tissue.
Sixty-five NTD-affected fetuses and 65 normal controls matched for gestational and maternal ages were collected. In brain tissue, global DNA methylation levels were significantly decreased in cases compared with controls (4.12 vs. 4.99%; p < 0.001). DNA hypomethylation (<4.35%) resulted in a significant 5.736-fold increased risk for NTDs (95% confidence interval, 1.731-19.009; p = 0.004). Nonisolated NTDs had lower levels of global DNA methylation than did isolated NTDs (3.77 vs. 4.70%; p = 0.022). After stratifying subjects by MTHFR genotype, we observed a skewed distribution of global DNA methylation levels. For genotype C/C, global DNA methylation status was the same in the two groups (4.51 vs. 4.72%; p = 0.687). For T/T, cases had significantly lower global methylation levels than did controls (5.23 vs. 3.79%; p < 0.001).
Global DNA hypomethylation in fetal brain tissue was associated with NTD-affected pregnancy. DNA methylation levels were correlated with NTD complexity. The MTHFR genotype contributed to global DNA hypomethylation. Birth Defects Research (Part A), 2010. (c) 2010 Wiley-Liss, Inc.
Birth Defects Research Part A Clinical and Molecular Teratology 07/2010; 88(7):575-81. · 2.27 Impact Factor
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ABSTRACT: Anembryonic pregnancy (AP; blighted ovum is the clinical term) is a common presentation of first-trimester abortion in China and affected women usually miscarry at 8-13 weeks. The association of plasma lead and the risk of AP in women from Shanxi Province, China, was examined. A case-control study was conducted, and plasma concentrations of lead were measured in blood obtained from women (n= 40) with AP and controls (n= 40) of normal pregnancy at their prenatal examination. AP was diagnosed by ultrasound scanning. The controls were identified and qualified by following up until a normal neonate was born. The mean concentration of lead in patients (53 microg/L, 95%CI: 4.3-6.3 microg/L) was slightly greater than the normal reference (50 microg/L, P < 0.01). The mean concentration of lead was higher in patients than in controls (53 versus 45 microg/L, P= 0.03). The lead concentration may be associated with the risk of AP, and should be paid more attention. Lead concentration that is slightly more than the standard limit may increase the risk of AP, but there may also be some other factors assisting lead to cause the occurrence of AP. Additional studies will be needed to confirm the findings and to find which factors were associated with the risk of AP when plasma lead is present.
Annals of the New York Academy of Sciences 11/2008; 1140:184-9. · 3.15 Impact Factor
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ABSTRACT: To characterize the intertype epitopes on human adenovirus (HAdV) hexon.
Based on computerized analysis on adenoviruses sequence of genomic alignment, antigenicity prediction and 3-D structure characteristics of hexon subunit, several peptides of hexon of adenoviruses were chosen to be synthesized or recombinant proteins of the hexon were expressed in E. coli by use of PGEX-5X. To identify the existence of intertype epitopes, the antisera raised with synthetic peptides or purified recombinant proteins were analyzed with Western blot and immunofluorescent assay.
The results of Western blot indicated that both peptide and recombinant antibodies showed specific reactivities with hexons of HADv-3, 4, 7 individually. Meanwhile, typical stain of immunofluorescence was found on HeLa cells infected with these HAdV by incubation with peptide as well as recombinant antibodies. Also, antibodies raised against peptide recognized the recombinant hexon protein in which a corresponding region of peptides was covered.
Most of the predicted intertype epitopes of HAdV hexon wer e exclusively found in synthetic peptides and recombinant proteins. These intertype epitopes showed to be continuous and sequential which could be employed for development of antibodies of diagnostic use.
Zhonghua shi yan he lin chuang bing du xue za zhi = Zhonghua shiyan he linchuang bingduxue zazhi = Chinese journal of experimental and clinical virology 04/2002; 16(1):44-7.
