Epigenetics and Preeclampsia: Defining Functional Epimutations in the Preeclamptic Placenta Related to the TGF-β Pathway.
Epigenetics and Preeclampsia: Defining Functional Epimutations in the Preeclamptic Placenta Related to the TGF-β Pathway.
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DOI：
10.1371/journal.pone.0141294
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Fry RC
中科院分区：
文献类型：
--
作者：
Martin E;Ray PD;Smeester L;Grace MR;Boggess K;Fry RC
先兆子痫是一种可能致命的妊娠疾病，影响着全球数百万妇女。控制血管生成的关键生物途径内的基因和蛋白质表达失调与先兆子痫的发展有关。 CpG 甲基化改变（一种表观突变）可能是该通路失调的基础。在本研究中，分析了先兆子痫病例和血压正常对照的胎盘组织的全基因组差异 CpG 甲基化和伴随的基因表达变化。一组 123 个基因（占所有 CpG 甲基化改变基因的 19.9%）与转录水平的功能变化相关。强调 CpG 甲基化和基因表达之间的复杂关系，这里高甲基化从来不与基因沉默相关，低甲基化也不总是与基因激活相关。此外，CpG 标记的基因组区域对于预测 CpG 甲基化和基因表达之间的关系很重要。这 123 个基因因参与转化生长因子 β (TGF-β) 信号通路而丰富，该信号通路是胎盘滋养层侵袭和迁移的已知调节因子。这是第一项确定 CpG 低甲基化是子痫前期胎盘中 TGF-β 相关基因表达激活剂的研究。结果表明功能性表突变与先兆子痫疾病状态相关，并且已鉴定的基因可能代表疾病的新生物标志物。
Preeclampsia is a potentially fatal pregnancy disorder affecting millions of women around the globe. Dysregulation in gene and protein expression within key biological pathways controlling angiogenesis has been implicated in the development of preeclampsia. Altered CpG methylation, a type of epimutation, may underlie this pathway dysregulation. In the present study, placental tissue from preeclamptic cases and normotensive controls was analyzed for genome-wide differential CpG methylation and concomitant changes in gene expression. A set of 123 genes, representing 19.9% of all genes with altered CpG methylation, was associated with functional changes in transcript levels. Underscoring the complex relationships between CpG methylation and gene expression, here hypermethylation was never associated with gene silencing, nor was hypomethylation always associated with gene activation. Moreover, the genomic region of the CpG mark was important in predicting the relationship between CpG methylation and gene expression. The 123 genes were enriched for their involvement in the transforming growth factor beta (TGF-β) signaling pathway, a known regulator of placental trophoblast invasion and migration. This is the first study to identify CpG hypomethylation as an activator of TGF-β-associated gene expression in the preeclamptic placenta. The results suggest functional epimutations are associated with preeclampsia disease status and the identified genes may represent novel biomarkers of disease.