Iglesias-Platas Isabel, Martin-Trujillo Alex, Petazzi Paolo, Guillaumet-Adkins Amy, Esteller Manel, Monk David
Servicio de Neonatología, Hospital Sant Joan de Déu, Fundació Sant Joan de Déu, Barcelona 08950, Spain,
Imprinting and Cancer Group.
Hum Mol Genet. 2014 Dec 1;23(23):6275-85. doi: 10.1093/hmg/ddu347. Epub 2014 Jul 3.
Genomic imprinting is the epigenetic process that results in monoallelic expression of genes depending on parental origin. These genes are known to be critical for placental development and fetal growth in mammals. Aberrant epigenetic profiles at imprinted loci, such as DNA methylation defects, are surprisingly rare in pregnancies with compromised fetal growth, while variations in transcriptional output from the expressed alleles of imprinted genes are more commonly reported in pregnancies complicated with intrauterine growth restriction (IUGR). To determine if PLAGL1 and HYMAI, two imprinted transcripts deregulated in Transient Neonatal Diabetes Mellitus, are involved in non-syndromic IUGR we compared the expression and DNA methylation levels in a large cohort of placental biopsies from IUGR and uneventful pregnancies. This revealed that despite appropriate maternal methylation at the shared PLAGL1/HYMAI promoter, there was a loss of correlation between PLAGL1 and HYMAI expression in IUGR. This incongruity was due to higher HYMAI expression in IUGR gestations, coupled with PLAGL1 down-regulation in placentas from IUGR girls, but not boys. The PLAGL1 protein is a zinc-finger transcription factor that has been shown to be a master coordinator of a genetic growth network in mice. We observe PLAGL1 binding to the H19/IGF2 shared enhancers in placentae, with significant correlations between PLAGL1 levels with H19 and IGF2 expression levels. In addition, PLAGL1 binding and expression also correlate with expression levels of metabolic regulator genes SLC2A4, TCF4 and PPARγ1. Our results strongly suggest that fetal growth can be influenced by altered expression of the PLAGL1 gene network in human placenta.
基因组印记是一种表观遗传过程，它导致基因根据亲本来源进行单等位基因表达。已知这些基因对哺乳动物的胎盘发育和胎儿生长至关重要。在胎儿生长受限的妊娠中，印记位点的异常表观遗传特征，如DNA甲基化缺陷，出奇地罕见，而印记基因表达等位基因的转录输出变化在合并宫内生长受限（IUGR）的妊娠中更常被报道。为了确定在短暂性新生儿糖尿病中失调的两个印记转录本PLAGL1和HYMAI是否参与非综合征性IUGR，我们比较了来自IUGR妊娠和正常妊娠的大量胎盘活检样本中的表达和DNA甲基化水平。这表明，尽管在共同的PLAGL1/HYMAI启动子处母体甲基化正常，但在IUGR中PLAGL1和HYMAI的表达之间失去了相关性。这种不一致是由于IUGR妊娠中HYMAI表达较高，以及IUGR女孩而非男孩的胎盘中PLAGL1下调。PLAGL1蛋白是一种锌指转录因子，已被证明是小鼠遗传生长网络的主要协调者。我们观察到PLAGL1与胎盘中的H19/IGF2共享增强子结合，PLAGL1水平与H19和IGF2表达水平之间存在显著相关性。此外，PLAGL1的结合和表达也与代谢调节基因SLC2A4、TCF4和PPARγ1的表达水平相关。我们的结果强烈表明，胎儿生长可能受到人胎盘中PLAGL1基因网络表达改变的影响。
