小胎龄比胎儿脑-胎盘比值异常时 VEGFA 和 LEP 的胎盘 DNA 甲基化差异。
Differential placental DNA methylation of VEGFA and LEP in small-for-gestational age fetuses with an abnormal cerebroplacental ratio.
机构信息
Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Neonatology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
出版信息
PLoS One. 2019 Aug 30;14(8):e0221972. doi: 10.1371/journal.pone.0221972. eCollection 2019.
BACKGROUND
In Fetal Growth Restriction 'fetal programming' may take place via DNA methylation, which has implications for short-term and long-term health outcomes. Small-for-gestational age fetuses are considered fetal growth restricted, characterized by brain-sparing when fetal Doppler hemodynamics are abnormal, expressed as a cerebroplacental ratio (CPR) <1. We aimed to determine whether brain-sparing is associated with altered DNA methylation of selected genes.
METHODS
We compared DNA methylation of six genes in 41 small-for-gestational age placentas with a normal or abnormal CPR. We selected EPO, HIF1A, VEGFA, LEP, PHLDA2, and DHCR24 for their role in angiogenesis, immunomodulation, and placental and fetal growth. DNA methylation was analyzed by pyrosequencing.
RESULTS
Growth restricted fetuses with an abnormal CPR showed hypermethylation of the VEGFA gene at one CpG (VEGFA-309, p = .001) and an overall hypomethylation of the LEP gene, being significant at two CpGs (LEP-123, p = .049; LEP-51, p = .020). No differences in methylation were observed for the other genes.
CONCLUSIONS
VEGFA and LEP genes are differentially methylated in placentas of small-for-gestational age fetuses with brain-sparing. Hypermethylation of VEGFA-309 in abnormal CPR-placentas could indicate successful compensatory mechanisms. Methylation of LEP-51 is known to suppress LEP expression. Hypomethylation in small-for-gestational age placentas with abnormal CPR may result in hyperleptinemia and predispose to leptin-resistance later in life.
背景
在胎儿生长受限中，“胎儿编程”可能通过 DNA 甲基化发生，这对短期和长期健康结果有影响。小于胎龄儿被认为是胎儿生长受限，当胎儿多普勒血流动力学异常时表现为脑保护，即脑胎盘比（CPR）<1。我们旨在确定脑保护是否与选定基因的 DNA 甲基化改变有关。
方法
我们比较了 41 例 CPR 正常或异常的小于胎龄儿胎盘的 6 个基因的 DNA 甲基化。我们选择 EPO、HIF1A、VEGFA、LEP、PHLDA2 和 DHCR24，因为它们在血管生成、免疫调节以及胎盘和胎儿生长中起作用。通过焦磷酸测序分析 DNA 甲基化。
结果
CPR 异常的生长受限胎儿的 VEGFA 基因在一个 CpG 上发生 hypermethylation（VEGFA-309，p=0.001），LEP 基因整体 hypomethylation，在两个 CpG 上有统计学意义（LEP-123，p=0.049；LEP-51，p=0.020）。其他基因未观察到甲基化差异。
结论
脑保护的小于胎龄儿胎盘的 VEGFA 和 LEP 基因存在差异甲基化。异常 CPR-胎盘中 VEGFA-309 的 hypermethylation 可能表明存在成功的补偿机制。LEP-51 的甲基化已知可抑制 LEP 的表达。异常 CPR 的小于胎龄儿胎盘的 hypomethylation 可能导致 leptinemia 增加，并使以后易发生 leptin-resistance。
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