Partial Loss of Genomic Imprinting Reveals Important Roles for Kcnq1 and Peg10 Imprinted Domains in Placental Development.
Partial Loss of Genomic Imprinting Reveals Important Roles for Kcnq1 and Peg10 Imprinted Domains in Placental Development.
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DOI：
10.1371/journal.pone.0135202
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Chaillet JR
中科院分区：
文献类型：
--
作者：
Koppes E;Himes KP;Chaillet JR
印记基因或其印记控制区的突变会导致印记基因表达的改变和胎盘结构的明显异常，表明基因组印记对胎盘发育的重要性。我们最近发现，在缺乏卵母细胞来源的DNMT10胞嘧啶甲基转移酶的情况下，与印记基因表达改变相关的胎盘异常的范围非常广，在植入前，DNMT10胞嘧啶甲基转移酶通常维持父母特有的印迹甲基化。DNMT1o的缺失部分减少了遗传印记甲基化，同时保留了印记基因及其ICR的遗传完整性。使用这个新的系统，我们采取了一种广泛和包容的方法来识别与胎盘发育有关的关键ICR，方法是将印记DNA甲基化缺失与中期妊娠窗口中异常的胎盘表型联系起来(E12.5-E15.5)。为此，我们使用EpiTYPER-MASS阵列技术测量了15个印迹配子差异甲基化结构域(GDMD)上的DNA CpG甲基化，这些结构域与已知ICR重叠，并将这些表观遗传学测量与组织形态缺陷联系起来。一些印记gDMD的甲基化，最著名的是Dlk1，在妊娠中期DNMT10缺陷的胎盘中几乎是正常的，这与这些DMDs上丢失甲基化的细胞对胎盘发育没有显著贡献的观点一致。然而，大多数印迹的gDMD在DNMT10缺失的胎盘中显示出广泛的甲基化缺失。观察到了两个显著的关联。首先，Peg10印迹gDMD处DNA甲基化的丢失与胚胎存活率和迷路体积的减少有关。其次，KCNQ1印迹gDMD的甲基化缺失与滋养层巨细胞(TGC)的扩张密切相关。我们认为，Peg10和KCNQ1 ICRs是孕中期胎盘功能的关键调节因子。
Mutations in imprinted genes or their imprint control regions (ICRs) produce changes in imprinted gene expression and distinct abnormalities in placental structure, indicating the importance of genomic imprinting to placental development. We have recently shown that a very broad spectrum of placental abnormalities associated with altered imprinted gene expression occurs in the absence of the oocyte–derived DNMT1o cytosine methyltransferase, which normally maintains parent-specific imprinted methylation during preimplantation. The absence of DNMT1o partially reduces inherited imprinted methylation while retaining the genetic integrity of imprinted genes and their ICRs. Using this novel system, we undertook a broad and inclusive approach to identifying key ICRs involved in placental development by correlating loss of imprinted DNA methylation with abnormal placental phenotypes in a mid-gestation window (E12.5-E15.5). To these ends we measured DNA CpG methylation at 15 imprinted gametic differentially methylated domains (gDMDs) that overlap known ICRs using EpiTYPER-mass array technology, and linked these epigenetic measurements to histomorphological defects. Methylation of some imprinted gDMDs, most notably Dlk1, was nearly normal in mid-gestation DNMT1o-deficient placentas, consistent with the notion that cells having lost methylation on these DMDs do not contribute significantly to placental development. Most imprinted gDMDs however showed a wide range of methylation loss among DNMT1o-deficient placentas. Two striking associations were observed. First, loss of DNA methylation at the Peg10 imprinted gDMD associated with decreased embryonic viability and decreased labyrinthine volume. Second, loss of methylation at the Kcnq1 imprinted gDMD was strongly associated with trophoblast giant cell (TGC) expansion. We conclude that the Peg10 and Kcnq1 ICRs are key regulators of mid-gestation placental function.