Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
J Clin Endocrinol Metab. 2011 Jan;96(1):E199-207. doi: 10.1210/jc.2010-1647. Epub 2010 Oct 20.
Increased epigenetic variability in the placenta may have evolved in response to its role in mediating the conflicting demands of the mother and fetus. One essential guardian of early pregnancy maintenance is the placental hormone human chorionic gonadotropin (HCG).
Among the four primate-specific duplicate HCGβ-coding genes, chorionic gonadotropin-β8 (CGB8) and chorionic gonadotropin-β5 (CGB5) jointly contribute 62-82% of the total HCGβ transcript pool. Because these genes share common features with known imprinted placenta-expressed loci, we addressed the role of epigenetic mechanisms affecting their action.
Parental origin of CGB5 and CGB8 transcripts and promoter methylation patterns were addressed in trophoblastic tissues from 23 mother-offspring duos and nine mother-father-offspring trios including the following: 1) third-trimester normal delivery at term (n = 14), 2) first-trimester elective termination of uncomplicated pregnancy (n = 10), and 3) first-trimester recurrent (≥3) miscarriage (n = 8).
A normal uncomplicated pregnancy was characterized by balanced, biallelic expression of CGB5 and CGB8. However, in three (two recurrent miscarriage and one early elective termination of uncomplicated pregnancy) of nine genetically informative cases of CGB5, monoallelic expression of maternal alleles and hemimethylated gene promoters were identified.
Our finding may represent a novel methylation allelic polymorphism or gain of imprinting in CGB5 promoter leading to expressional silencing of paternal alleles and increasing susceptibility to pregnancy loss. Aberrant methylation patterns in placenta may result from random reprogramming defects affecting normal implantation process. Alternatively, methylation allelic polymorphism in the placenta favoring the failure of pregnancy may arise as a response to cellular stress caused by, in general, aneuploidy or conditions in placental-maternal interface.
胎盘的表观遗传变异性增加可能是为了适应其在调节母体和胎儿之间冲突需求的作用而进化的。维持早期妊娠的一个重要守护者是胎盘激素人绒毛膜促性腺激素（hCG）。
在四种灵长类特异性 hCGβ 编码基因中，绒毛膜促性腺激素-β8（CGB8）和绒毛膜促性腺激素-β5（CGB5）共同贡献了总 hCGβ 转录本池的 62-82%。由于这些基因与已知的印迹胎盘表达基因座具有共同的特征，我们研究了影响其作用的表观遗传机制的作用。
在 23 对母婴和 9 对母婴-父代三代中，研究了绒毛膜组织中 CGB5 和 CGB8 转录物的亲本来源和启动子甲基化模式，这些三代包括以下内容：1）足月正常分娩（n=14），2）孕早期选择终止无并发症妊娠（n=10），3）孕早期（≥3）复发性流产（n=8）。
正常的无并发症妊娠表现为 CGB5 和 CGB8 的平衡、双等位基因表达。然而，在 9 个具有遗传信息的 CGB5 病例中的三个（两个复发性流产和一个早期无并发症妊娠选择终止）中，鉴定出母体等位基因的单等位基因表达和半甲基化基因启动子。
我们的发现可能代表了 CGB5 启动子中一种新的甲基化等位基因多态性或印迹获得，导致父系等位基因的表达沉默，并增加妊娠丢失的易感性。胎盘中的异常甲基化模式可能是由于影响正常植入过程的随机重编程缺陷引起的。或者，有利于妊娠失败的胎盘甲基化等位基因多态性可能是对细胞应激的一种反应，这种应激通常是由非整倍体或胎盘-母体界面的条件引起的。
