Unbalanced placental expression of imprinted genes in human intrauterine growth restriction
Unbalanced placental expression of imprinted genes in human intrauterine growth restriction
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DOI：
10.1016/j.placenta.2005.07.004
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发表时间：
2006-06-01
期刊：
影响因子：
3.8
通讯作者：
Tycko, B.
中科院分区：
文献类型：
--
作者：
McMinn, J.;Wei, M.;Tycko, B.
印记基因控制小鼠和罕见人类综合征的胎儿和胎盘生长，但这些基因在散发性宫内生长受限（IUGR）中的作用研究较少。我们通过北方印迹法在38例IUGR相关胎盘和75例非IUGR胎盘中测定了来自母系表达的印迹基因PHLDA 2与来自父系表达的印迹基因MEST的mRNA比率，发现IUGR患者PHLDA 2/MEST mRNA比率增加（p = 0.0001）。PHLDA 2和MEST的表达改变并不伴随着DNA甲基化的变化，在他们的印记中心，和免疫组化显示PHLDA 2蛋白适当限制绒毛和中间细胞滋养层在IUGR胎盘。接下来，我们使用Affytron U133 A微阵列对14例母体血管灌注不足的IUGR胎盘和15例非IUGR胎盘的mRNA表达进行了全基因组调查。在这个系列中，6个印迹基因的差异表达的方差分析与Benjamini-Hochberg错误发现率为0.05，与表达增加PHLDA 2和表达减少MEST，MEG 3，GATM，GNAS和PLAGL 1在IUGR胎盘。在较低的意义上，我们发现IUGR病例中IGF 2 mRNA降低，CDKN 1C mRNA升高。我们通过北方印迹证实了IUGR胎盘中MEG 3非翻译RNA的显著减少。除了印迹基因之外，微阵列数据突出了在IUGR与非IUGR胎盘中差异表达的内分泌信号传导（LEP，CRH，HPGD，INHBA），组织生长（IGF 1），免疫调节（INDO，PSG家族基因），氧化代谢（GLRX），血管功能（AGTR 1，DSCR 1）和代谢物转运（SLC家族溶质载体）中起作用的非印迹基因。
Imprinted genes control fetal and placental growth in mice and in rare human syndromes, but the role of these genes in sporadic intrauterine growth restriction (IUGR) is less well-studied. We measured the ratio of mRNA from a maternally expressed imprinted gene, PHLDA2, to that from a paternally expressed imprinted gene, MEST, by Northern blotting in 38 IUGR-associated placentae and 75 non-IUGR placentae and found an increase in the PHLDA2/MEST mRNA ratio in IUGR (p = 0.0001). Altered expression of PHLDA2 and MEST was not accompanied by changes in DNA methylation within their imprinting centers, and immunohistochemistry showed PHLDA2 protein appropriately restricted to villous and intermediate cytotrophoblast in the IUGR placentae. We next did a genome-wide survey of mRNA expression in 14 IUGR placentae with maternal vascular under-perfusion compared to 15 non-IUGR placentae using Affymetrix U133A microarrays. In this series six imprinted genes were differentially expressed by ANOVA with a Benjamini-Hochberg false discovery rate of 0.05, with increased expression of PHLDA2 and decreased expression of MEST, MEG3, GATM, GNAS and PLAGL1 in IUGR placentae. At lower significance, we found IGF2 mRNA decreased and CDKN1C mRNA increased in the IUGR cases. We confirmed the significant reduction in MEG3 non-translated RNA in IUGR placentae by Northern blotting. In addition to imprinted genes, the microarray data highlighted non-imprinted genes acting in endocrine signaling (LEP, CRH, HPGD, INHBA), tissue growth (IGF1), immune modulation (INDO, PSG-family genes), oxidative metabolism (GLRX), vascular function (AGTR1, DSCR1) and metabolite transport (SLC-family solute carriers) as differentially expressed in IUGR vs. non-IUGR placentae.