Aberrant methylation of H19-DMR acquired after implantation was dissimilar in soma versus placenta of patients with Beckwith-Wiedemann syndrome
Aberrant methylation of H19-DMR acquired after implantation was dissimilar in soma versus placenta of patients with Beckwith-Wiedemann syndrome
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DOI：
10.1002/ajmg.a.35335
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发表时间：
2012-07-01
影响因子：
2
通讯作者：
Soejima, Hidenobu
中科院分区：
文献类型：
--
作者：
Higashimoto, Ken;Nakabayashi, Kazuhiko;Soejima, Hidenobu
h19差异甲基化区（H19-DMR）的甲基化增益（GOM）是一种印迹相关疾病BeckwithWiedemann综合征（BWS）的几种致病改变之一。在大多数H19-DMR发生表观遗传改变的患者中，介导GOM的时间和机制尚不清楚。为了澄清这一点，我们分析了两名自然受孕的散发性BWS患者的体细胞组织和胎盘印记控制区的甲基化。两名患者的母体H19-DMR异常和可变高甲基化，表明表观遗传嵌合体。胎盘中的异常甲基化水平始终低于血液和皮肤。镶嵌甲基化和不一致甲基化强烈表明，当全基因组从头甲基化正常发生时，异常的超甲基化发生在植入后。我们预计H19-DMR异常的新生高甲基化在胚胎中比在胎盘中发生的程度更大，因为这通常是新生甲基化的情况。此外，在分析的16个原发印迹DMR中，除了患者2的胎盘脉络瘤中的NNAT DMR外，只有H19-DMR出现了异常甲基化。据我们所知，这些是提示H19-DMR何时发生GOM的第一个数据。(C) 2012 Wiley期刊公司
Gain of methylation (GOM) at the H19-differentially methylated region (H19-DMR) is one of several causative alterations in BeckwithWiedemann syndrome (BWS), an imprinting-related disorder. In most patients with epigenetic changes at H19-DMR, the timing of and mechanism mediating GOM is unknown. To clarify this, we analyzed methylation at the imprinting control regions of somatic tissues and the placenta from two unrelated, naturally conceived patients with sporadic BWS. Maternal H19-DMR was abnormally and variably hypermethylated in both patients, indicating epigenetic mosaicism. Aberrant methylation levels were consistently lower in placenta than in blood and skin. Mosaic and discordant methylation strongly suggested that aberrant hypermethylation occurred after implantation, when genome-wide de novo methylation normally occurs. We expect aberrant de novo hypermethylation of H19-DMR happens to a greater extent in embryos than in placentas, as this is normally the case for de novo methylation. In addition, of 16 primary imprinted DMRs analyzed, only H19-DMR was aberrantly methylated, except for NNAT DMR in the placental chorangioma of Patient 2. To our knowledge, these are the first data suggesting when GOM of H19-DMR occurs. (C) 2012 Wiley Periodicals, Inc.