足月和早产子痫前期中人类 VEGF、FLT-1 和 KDR 基因的胎盘甲基化和表达差异。
Differential placental methylation and expression of VEGF, FLT-1 and KDR genes in human term and preterm preeclampsia.
机构信息
Department of Nutritional Medicine, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune, 411043, India.
Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research (CSIR), Hyderabad, 500007, India.
出版信息
Clin Epigenetics. 2013 Apr 26;5(1):6. doi: 10.1186/1868-7083-5-6.
BACKGROUND
Preeclampsia, a pregnancy complication of placental origin is associated with altered expression of angiogenic factors and their receptors. Recently, there is considerable interest in understanding the role of adverse intrauterine conditions in placental dysfunction and adverse pregnancy outcomes. Since we have observed changes in placental global DNA methylation levels in preeclampsia, this study was undertaken to examine gene promoter CpG methylation and expression of several angiogenic genes.We recruited 139 women comprising, 46 normotensive women with term delivery (≥37 weeks), 45 women with preeclampsia delivering preterm (<37 weeks) and 48 women with preeclampsia delivering at term. Expression levels and promoter CpG methylation of VEGF, FLT-1 and KDR genes in placentae from respective groups were determined by Taqman-based quantitative real time PCR and by the Sequenom® EpiTYPER™ technology respectively.
RESULTS
We observed several differentially methylated CpG sites in the promoter regions of VEGF, FLT-1 and KDR between the normotensive and preeclampsia groups. We specifically observed hypomethylated CpGs in the promoter region and an increased expression of VEGF gene between term and preterm preeclampsia. However, mean promoter CpG methylation could not account for the higher expression of FLT-1 and KDR in preterm preeclampsia as compared to normotensive group.
CONCLUSIONS
Our data indicates altered DNA methylation patterns in the VEGF, FLT-1 and KDR genes in preeclampsia as compared to the normotensive group, which could be involved in the pathophysiology of preeclampsia. Hypomethylation of VEGF promoter and consequent upregulation of VEGF mRNA levels could be a compensatory mechanism to restore normal angiogenesis and blood flow in preterm preeclampsia. This study suggests a role of altered DNA methylation in placental angiogenesis and in determining adverse pregnancy outcomes.
背景
子痫前期是一种胎盘源性的妊娠并发症，与血管生成因子及其受体的表达改变有关。最近，人们对理解不良宫内环境在胎盘功能障碍和不良妊娠结局中的作用产生了浓厚的兴趣。由于我们已经观察到子痫前期胎盘整体 DNA 甲基化水平的变化，因此进行了这项研究，以检查几个血管生成基因的启动子 CpG 甲基化和表达。
我们招募了 139 名女性，包括 46 名血压正常的足月分娩（≥37 周）女性、45 名早产（<37 周）子痫前期患者和 48 名足月分娩的子痫前期患者。通过 Taqman 定量实时 PCR 和 Sequenom® EpiTYPER™ 技术分别测定各组胎盘中 VEGF、FLT-1 和 KDR 基因的表达水平和启动子 CpG 甲基化。
结果
我们观察到 VEGF、FLT-1 和 KDR 基因启动子区域在血压正常组和子痫前期组之间存在几个差异甲基化的 CpG 位点。我们特别观察到在足月和早产子痫前期之间，VEGF 基因启动子区域的低甲基化和 VEGF 基因表达增加。然而，与血压正常组相比，早产子痫前期中 FLT-1 和 KDR 基因的高表达并不能用平均启动子 CpG 甲基化来解释。
结论
与血压正常组相比，子痫前期患者的 VEGF、FLT-1 和 KDR 基因存在改变的 DNA 甲基化模式，这可能与子痫前期的病理生理学有关。VEGF 启动子的低甲基化和随后的 VEGF mRNA 水平上调可能是一种代偿机制，以恢复早产子痫前期的正常血管生成和血流。这项研究表明，DNA 甲基化改变在胎盘血管生成和决定不良妊娠结局中起作用。
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