A New Perspective on Neural Tube Defects: Folic Acid and MicroRNA Misexpression

Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA.
genesis (Impact Factor: 2.02). 05/2010; 48(5):282-94. DOI: 10.1002/dvg.20623
Source: PubMed


Neural tube defects (NTDs) are the second most common birth defects in the United States. It is well known that folic acid supplementation decreases about 70% of all NTDs, although the mechanism by which this occurs is still relatively unknown. The current theory is that folic acid deficiency ultimately leads to depletion of the methyl pool, leaving critical genes unmethylated, and, in turn, their improper expression leads to failure of normal neural tube development. Recently, new studies in human cell lines have shown that folic acid deficiency and DNA hypomethylation can lead to misexpression of microRNAs (miRNAs). Misexpression of critical miRNAs during neural development may lead to a subtle effect on neural gene regulation, causing the sometimes mild to severely debilitating range of phenotypes exhibited in NTDs. This review seeks to cohesively integrate current information regarding folic acid deficiency, methylation cycles, neural development, and miRNAs to propose a potential model of NTD formation. In addition, we have examined the relevant gene pathways and miRNAs that are predicted to affect them, and based on our investigation, we have devised a basic template of experiments for exploring the idea that miRNA misregulation may be linked to folic acid deficiency and NTDs.

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Available from: G. Ian Gallicano, Oct 02, 2014
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    • "Recent works have found that dihydrofolate reductase, target enzymes of inhibition by pemetrexed, is regulated at the translational level by miR-24 (Shookhoff and Gallicano, 2010). Further findings revealed that miR-22 and miR-34a target methylenetetrahydrofolate reductase (MTHFR), key enzyme in folate metabolism (Shookhoff and Gallicano, 2010; Stone et al., 2011). MTHFR polymorphisms have been associated with clinical outcome in NSCLC patients treated with pemetrexed (Kim et al., 2010; Franchina et al., 2011; Hou et al., 2012; Tiseo et al., 2012). "
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    ABSTRACT: Pemetrexed has been widely used in patients with advanced non small cell lung cancer (NSCLC). The clinical relevance of polymorphisms of folate pathway genes for pemetrexed metabolism have not been fully elucidated yet. The aim of this study was to evaluate the expression levels of circulating miR-22, miR-24 and miR-34a, possibly involved in folate pathway, in NSCLC patients treated with pemetrexed compared with healthy controls and to investigate their impact on patient clinical outcomes. A total of 22 consecutive patients with advanced NSCLC, treated with pemetrexed-based chemotherapy and 27 age and sex matched healthy controls were included in this preliminary analysis. miR-22, miR-24 and miR-34a targets were identified by TargetScan 6.2 algorithm, validating the involvement of these microRNAs in folate pathway. MicroRNAs were isolated from whole blood and extracted with miRNAeasy Mini Kit (Qiagen). miRNA profiling was performed using Real-Time PCR. SPSS 17 was used to data analysis. miR-22, miR-24 and miR-34a were found upregulated (p < 0.05) in NSCLC patients versus healthy controls. Higher expression levels were recorded for miR-34a. Nevertheless, significantly higher miR-22 expression was observed in patients developing progressive disease (p = 0.03). No significant associations with clinical outcome were recorded for miR-24 and miR-34a. Albeit preliminary, these data support the involvement of miR-22, miR-24 and miR-34a in advanced NSCLC. The correlation between high expression of miR-22 in whole blood and the lack of response in pemetrexed treated NSCLC patients indicates that miR-22 could represent a novel predictive biomarker for pemetrexed-based treatment. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Jun 2013 · Journal of Cellular Physiology
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    • "They have been implicated in various physiological processes. Abrupt expression of miRNAs causes physiological disturbances, such as developmental defects and diseases [2], [3]. A miRNA gene can reside in an intergenic region, in an intron of a gene, or in a transposon region. "
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    ABSTRACT: microRNAs (miRNAs) are implicated in regulation of many cellular processes. miRNAs are processed to their mature functional form in a step-wise manner by multiple proteins and cofactors in the nucleus and cytoplasm. Many miRNAs are conserved across vertebrates. Mature miRNAs have recently been characterized in Atlantic halibut (Hippoglossus hippoglossus L.). The aim of this study was to identify and characterize precursor miRNA (pre-miRNAs) and miRNA targets in this non-model flatfish. Discovery of miRNA precursor forms and targets in non-model organisms is difficult because of limited source information available. Therefore, we have developed a methodology to overcome this limitation. Genomic DNA and small transcriptome of Atlantic halibut were sequenced using Roche 454 pyrosequencing and SOLiD next generation sequencing (NGS), respectively. Identified pre- miRNAs were further validated with reverse-transcription PCR. miRNA targets were identified using miRanda and RNAhybrid target prediction tools using sequences from public databases. Some of miRNA targets were also identified using RACE-PCR. miRNA binding sites were validated with luciferase assay using the RTS34st cell line. We obtained more than 1.3 M and 92 M sequence reads from 454 genomic DNA sequencing and SOLiD small RNA sequencing, respectively. We identified 34 known and 9 novel pre-miRNAs. We predicted a number of miRNA target genes involved in various biological pathways. miR-24 binding to kisspeptin 1 receptor-2 (kiss1-r2) was confirmed using luciferase assay. This study demonstrates that identification of conserved and novel pre-miRNAs in a non-model vertebrate lacking substantial genomic resources can be performed by combining different next generation sequencing technologies. Our results indicate a wide conservation of miRNA precursors and involvement of miRNA in multiple regulatory pathways, and provide resources for further research on miRNA in non-model animals.
    Full-text · Article · Apr 2013 · PLoS ONE
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    • "Over-expression of miR-720 may result in suppression of Dnmt3a, which would further exacerbate hypomethylation, and hence, contribute to a loss of differentiation, leading to alter normal neural development (Okano et al. 1999; Au et al. 2010). It has been known that folic acid deficiency is a main cause of NTDs, and the reduction of genes methylation plays an important role in mechanisms underlying the effect of folic acid in relation to NTDs (Shookhoff and Gallicano 2010; Stone et al. 2011). Some potential targets of the six miRNAs such as DNMT3A, CBS, MTHFD2, and FPGS are implicated in the methylation or folate homeostasis; thus, the miRNA misexpression may contribute to the NTDs by modulating methylation or folate metabolism. "
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    ABSTRACT: J. Neurochem. (2012) 122, 641–649. The discovery of placental microRNAs (miRNAs) in maternal serum has opened up new possibilities for non-invasive prenatal diagnosis. However, the expression of miRNAs in the serum of pregnant women with fetuses with neural tube defects (NTDs) has not been characterized. In this article, we explored serum miRNAs as potential biomarkers in the serum of pregnant women with NTD fetuses. By using a miRNA microarray that covers 887 human miRNAs, we revealed 17 miRNAs with significant change in expression in serum of pregnant women with NTD fetuses and women with normal pregnancies. Quantitative reverse-transcription PCR (qRT-PCR) analysis validated that the expression for six miRNAs (miR-142-3p, miR-144, miR-720, miR-575, miR-765, and miR-1182) was up-regulated and that for miR-1275 was down-regulated. To determine whether these miRNAs were related to pregnancy, we compared the miRNA levels in pre- and post-delivery maternal serum samples. Six of these miRNAs were rapidly reduced in post-delivery serum (p < 0.05). Moreover, by receiver operating characteristic (ROC) curve analysis, the area under the ROC curve (AUC) of combining these six miRNAs was 0.803 (p < 0.001). Thus, we reveal six pregnancy-associated miRNAs that are deregulated in the serum of pregnant women with NTD fetuses and highlight the clinical potential of serum miRNAs as biomarkers for diagnosis and prognostication of fetal NTDs.
    Full-text · Article · May 2012 · Journal of Neurochemistry
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