Characterization of DNA methylation errors in patients with imprinting disorders conceived by assisted reproduction technologies
Characterization of DNA methylation errors in patients with imprinting disorders conceived by assisted reproduction technologies
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DOI：
10.1093/humrep/des197
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发表时间：
2012-08-01
影响因子：
6.1
通讯作者：
Arima, Takahiro
中科院分区：
文献类型：
--
作者：
Hiura, Hitoshi;Okae, Hiroaki;Arima, Takahiro
与辅助生殖技术（ART）相关的罕见印迹疾病的发病率增加。ART婴儿印迹基因座的表观遗传变化的鉴定表明，这些技术本身可能使胚胎易于获得印迹错误和疾病。然而，仍然不知道这些印记错误是在什么时候出现的，或者风险因素。2009年，我们对四种著名的印记疾病进行了日本全国流行病学研究，以确定与ART的任何关联。使用亚硫酸氢盐测序，我们检测了Beckwith患者已知印迹基因座内22个配子差异甲基化区域（gDMR）的DNA甲基化状态，维综合征（BWS，n 1）和Silver-Russell综合征我们发现，与ART相关的BWS和SRS的发生率增加了10倍。大多数ART病例在多个印记基因座上显示异常的DNA甲基化模式，包括母亲和父亲的gDMR（5/6），具有高甲基化和低甲基化事件（5/6）以及嵌合甲基化错误（5/6）。虽然我们的研究可能受到样本数量较少的限制，但许多变化是镶嵌的这一事实表明它们发生在受精后。相比之下，自然受孕的患者很少表现出类似的马赛克改变模式。由于这些印记疾病的疾病表型不同，自然受孕或ART后受孕的患者之间甲基化模式的差异并不明显。ART和BWS/SRS之间可能存在关联，我们观察到ART后更广泛的基因组印记破坏。考虑到主要的表观遗传事件，ART后印记疾病的频率增加可能并不奇怪。在发育早期，表观基因组最脆弱的时候。
There is an increased incidence of rare imprinting disorders associated with assisted reproduction technologies (ARTs). The identification of epigenetic changes at imprinted loci in ART infants has led to the suggestion that the techniques themselves may predispose embryos to acquire imprinting errors and diseases. However, it is still unknown at what point(s) these imprinting errors arise, or the risk factors.In 2009 we conducted a Japanese nationwide epidemiological study of four well-known imprinting diseases to determine any association with ART. Using bisulfite sequencing, we examine the DNA methylation status of 22 gametic differentially methylated regions (gDMRs) located within the known imprinted loci in patients with Beckwith-Wiedemann syndrome (BWS, n 1) and also Silver-Russell syndrome (SRS, n 5) born after ART, and compared these with patients conceived naturally.We found a 10-fold increased frequency of BWS and SRS associated with ART. The majority of ART cases showed aberrant DNA methylation patterns at multiple imprinted loci both maternal and paternal gDMRs (5/6), with both hyper- and hypomethylation events (5/6) and also mosaic methylation errors (5/6). Although our study may have been limited by a small sample number, the fact that many of the changes were mosaic suggested that they occurred after fertilization. In contrast, few of the patients who were conceived naturally exhibited a similar pattern of mosaic alterations. The differences in methylation patterns between the patients who were conceived naturally or after ART did not manifest due to the differences in the disease phenotypes in these imprinting disorders.A possible association between ART and BWS/SRS was found, and we observed a more widespread disruption of genomic imprints after ART. The increased frequency of imprinting disorders after ART is perhaps not surprising given the major epigenetic events that take place during early development at a time when the epigenome is most vulnerable.