Altered gene expression and methylation of the human chromosome 11 imprinted region in small for gestational age (SGA) placentae
Altered gene expression and methylation of the human chromosome 11 imprinted region in small for gestational age (SGA) placentae
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DOI：
10.1016/j.ydbio.2008.04.025
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发表时间：
2008-08-01
影响因子：
2.7
通讯作者：
Weksberg, Rosanna
中科院分区：
文献类型：
--
作者：
Guo, Lin;Choufani, Sanaa;Weksberg, Rosanna
众所周知，印迹基因对哺乳动物的胎盘发育和胎儿生长至关重要，但没有证据表明胎盘中的原发性表观遗传异常会损害人类胎儿的生长。印迹基因表现出亲本起源特异性等位基因的表达，这是表观遗传调控的，即原始DNA序列的外在因素。为了对胎盘和脐带血组织中胎儿生长不良进行表观遗传学分析，我们首先建立了胎盘和新生儿血液中两个印迹集群（KvDMR和H19 DMR）油染色体11p15的甲基化和印迹基因表达的组织特异性模式，包括20例对照病例和24例胎龄小（SGA）病例。我们证实，在正常人类胎盘中，H19启动子是未甲基化的。相比之下，大多数其他人体组织显示父系甲基化。此外，我们发现IGF2 DMR2在大多数人类组织中也发生了父本甲基化，但在胎盘中表现出低甲基化。然而，在新生儿血液DNA中，这两个区域在大多数其他组织中保持不同的甲基化状态。值得注意的是，我们已经能够证明胎盘确实在印迹控制区H19 DMR和KvDMR保持差异甲基化。值得注意的是，在一个SGA胎盘中，我们发现H19 DMR的甲基化改变和伴随的H19基因双等位基因表达，这表明H19印迹的缺失是人类胎儿生长不良的一个原因。特别有趣的是，我们还证明了所有SGA胎盘中IGF2 mRNA水平的下降，并且在大多数情况下，这种下降与h19调节无关。英国皇家版权所有(C) 2008 Elsevier Inc.出版版权所有。
Imprinted genes are known to be Crucial for placental development and fetal growth in mammals, but no primary epigenetic abnormality in placenta has been documented to compromise human fetal growth. Imprinted genes demonstrate parent-of-origin-specific allelic expression that is epigenetically regulated i.e. extrinsic to the primary DNA sequence. To undertake an epigenetic analysis of poor fetal growth in placentae and cord blood tissues, we first established the tissue-specific patterns of methylation and imprinted gene expression for two imprinting clusters (KvDMR and H19 DMR) oil chromosome 11p15 in placentae and neonatal blood for 20 control cases and 24 Small for Gestational Age (SGA) cases. We confirmed that, in normal human placenta, the H19 promoter is unmethylated. In contrast, most other human tissues show paternal methylation. In addition, we showed that the IGF2 DMR2, also paternally methylated in most human tissues, exhibits hypomethylation in placentae. However, in neonatal blood DNA, these two regions maintain the differential methylation status seen in most other tissues. Significantly, we have been able to demonstrate that placenta does maintain differential methylation at the imprinting control regions H19 DMR and KvDMR. Of note, in one SGA placenta, we found a methylation alteration at the H19 DMR and concomitant biallelic expression of the H19 gene, suggesting that loss of imprinting at H19 is one cause of poor fetal growth in humans. Of particular interest, we demonstrated also a decrease in IGF2 mRNA levels in all SGA placentae and showed that the decrease is, in most cases, independent of H 19 regulation. Crown Copyright (C) 2008 Published by Elsevier Inc. All rights reserved.