Diplas Andreas I, Lambertini Luca, Lee Men-Jean, Sperling Rhoda, Lee Yin Leng, Wetmur James, Chen Jia
Departments of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Epigenetics. 2009 May 16;4(4):235-40. doi: 10.4161/epi.9019. Epub 2009 May 14.
Genomic imprinting refers to silencing of one parental allele in the zygotes of gametes depending upon the parent of origin. Loss of imprinting (LOI) is the gain of function from the silent allele that can have a maximum effect of doubling the gene dosage. LOI may play a significant role in the etiology of intrauterine growth restriction (IUGR). Using placental tissue from ten normal and seven IUGR pregnancies, we conducted a systematic survey of the expression of a panel of 74 "putatively" imprinted genes using quantitative RT-PCR. We found that 52/74 ( approximately 70%) of the genes were expressed in human placentas. Nine of the 52 (17%) expressed genes were significantly differentially expressed between normal and IUGR placentas; five were upregulated (PHLDA2, ILK2, NNAT, CCDC86, PEG10) and four downregulated (PLAGL1, DHCR24, ZNF331, CDKAL1). We also assessed LOI profile of 14 imprinted genes in 14 normal and 24 IUGR placentas using a functional and sensitive assay developed in our laboratory. Little LOI was observed in any placentas for five of the genes (PEG10, PHLDA2, MEG3, EPS15, CD44). With the 149 heterozygosities examined, 40 (26.8%) exhibited LOI >3%. Some genes exhibited frequent LOI in placentas regardless of the disease status (IGF2, TP73, MEST, SLC22A18, PEG3), while others exhibited LOI only in IUGR placentas (PLAGL1, DLK1, H19, SNRPN). Importantly, there was no correlation between gene expression and LOI profile. Our study suggests that genomic imprinting may play a role in IUGR pathogenesis, but mechanisms other than LOI may contribute to dysregulation of imprinted genes.
基因组印记是指根据配子的亲代来源，在受精卵中使一个亲代等位基因沉默。印记丢失（LOI）是指沉默等位基因功能的获得，其最大效应可能是使基因剂量加倍。LOI可能在宫内生长受限（IUGR）的病因中起重要作用。我们使用来自10例正常妊娠和7例IUGR妊娠的胎盘组织，通过定量逆转录聚合酶链反应（RT-PCR）对一组74个“假定”印记基因的表达进行了系统调查。我们发现52/74（约70%）的基因在人胎盘中表达。在这52个表达基因中，有9个（17%）在正常胎盘和IUGR胎盘中存在显著差异表达；5个上调（PHLDA2、ILK2、NNAT、CCDC86、PEG10），4个下调（PLAGL1、DHCR24、ZNF331、CDKAL1）。我们还使用在我们实验室开发的一种功能灵敏的检测方法，评估了14例正常胎盘和24例IUGR胎盘中14个印记基因的LOI情况。在任何胎盘中，5个基因（PEG10、PHLDA2、MEG3、EPS15、CD44）几乎未观察到LOI。在所检测的149个杂合位点中，40个（26.8%）表现出LOI>3%。一些基因在胎盘中无论疾病状态如何都频繁出现LOI（IGF2、TP73、MEST、SLC22A18、PEG3），而另一些基因仅在IUGR胎盘中出现LOI（PLAGL1、DLK1、H19、SNRPN）。重要的是，基因表达与LOI情况之间没有相关性。我们的研究表明，基因组印记可能在IUGR发病机制中起作用，但除LOI之外的其他机制可能导致印记基因的失调。
