A hierarchical analysis of transcriptome alterations in intrauterine growth restriction (lUGR) reveals common pathophysiological pathways in mammals
A hierarchical analysis of transcriptome alterations in intrauterine growth restriction (lUGR) reveals common pathophysiological pathways in mammals
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DOI：
10.1002/path.2233
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发表时间：
2007-11-01
影响因子：
7.3
通讯作者：
Vaiman, D.
中科院分区：
文献类型：
--
作者：
Buffat, C.;Mondon, F.;Vaiman, D.
宫内生长受限（IUGR）是一种常见疾病，影响高达10%的人类妊娠，并导致围产期发病率和死亡率增加。此外，低出生体重是成年代谢综合征的重要原因。雌性大鼠妊娠期间的蛋白质耗竭已被广泛用作人类IUGR的模型。通过对对照和蛋白质剥夺大鼠胎盘的转录组分析，我们能够鉴定出2543个修饰超过2.5倍的转录本（1347个诱导转录本和1196个抑制转录本）。自动功能分类使我们能够识别影响染色体结构、转录、细胞内转运、蛋白质修饰和凋亡的诱导基因簇。特别是，我们认为存在一个复杂的平衡调节细胞凋亡。在受抑制的基因中，我们注意到几组基因涉及免疫、信号传导和有毒化学物质的降解。这些观察结果表明，IUGR胎盘对外部攻击的抵抗力下降。最受诱导和最受抑制的基因的启动子进行了对比，其组成在假定的转录因子结合位点。锌指（ZNF）蛋白和Pdx 1（胰腺和十二指肠同源盒蛋白1）推定结合位点过度表达。因此，Pdx 1和高比例的ZNF基因在转录水平上被诱导。对ZNF启动子的类似分析显示Tata盒结合蛋白（Tbp）的推定结合位点的存在增加。同样，我们发现Tbp和TBP相关因子（Tafs）在IUGR胎盘中上调。此外，人IUGR和对照胎盘样品显示人orthotropic ZNF和PDX 1是转录诱导的，特别是在非血管性IUGR中。免疫组化显示PDX 1在IUGR人胎盘中的表达增加。总之，我们的方法允许的假设的层次结构的基因诱导/抑制，导致大量的转录改变在IUGR胎盘，在人类和啮齿动物的命题。版权所有（C）2007英国和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Intra-uterine growth restriction (IUGR) is a frequent disease, affecting up to 10% of human pregnancies and responsible for increased perinatal morbidity and mortality. Moreover, low birth weight is an important cause of the metabolic syndrome in the adult. Protein depletion during the gestation of rat females has been widely used as a model for human IUGR. By transcriptome analysis of control and protein-deprived rat placentas, we were able to identify 2543 transcripts modified more than 2.5 fold (1347 induced and 1196 repressed). Automatic functional classification enabled us to identify clusters of induced genes affecting chromosome structure, transcription, intracellular transport, protein modifications and apoptosis. In particular, we suggest the existence of a complex balance regulating apoptosis. Among repressed genes, we noted several groups of genes involved in immunity, signalling and degradation of noxious chemicals. These observations suggest that IUGR placentas have a decreased resistance to external aggression. The promoters of the most induced and most repressed genes were contrasted for their composition in putative transcription factor binding sites. There was an over-representation of Zn finger (ZNF) proteins and Pdx1 (pancreatic and duodenal homeobox protein 1) putative binding sites. Consistently, Pdx1 and a high proportion of ZNF genes were induced at the transcriptional level. A similar analysis of ZNF promoters showed an increased presence of putative binding sites for the Tata box binding protein (Tbp). Consistently again, we showed that the Tbp and TBP-associated factors (Tafs) were up-regulated in IUGR placentas. Also, samples of human IUGR and control placentas showed that human orthologous ZNFs and PDX1 were transcriptionnally induced, especially in non-vascular IUGR. Immunohistochemistry revealed increased expression of PDX1 in IUGR human placentas. In conclusion, our approach permitted the proposition of hypotheses on a hierarchy of gene inductions/repressions leading to massive transcriptional alterations in the IUGR placenta, in humans and in rodents. Copyright (C) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.