Evolutionary origins of the placental expression of chromosome 19 cluster galectins and their complex dysregulation in preeclampsia.
Evolutionary origins of the placental expression of chromosome 19 cluster galectins and their complex dysregulation in preeclampsia.
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DOI：
10.1016/j.placenta.2014.07.015
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发表时间：
2014-11
期刊：
影响因子：
3.8
通讯作者：
Bohn H
中科院分区：
文献类型：
--
作者：
Than NG;Romero R;Xu Y;Erez O;Xu Z;Bhatti G;Leavitt R;Chung TH;El-Azzamy H;LaJeunesse C;Wang B;Balogh A;Szalai G;Land S;Dong Z;Hassan SS;Chaiworapongsa T;Krispin M;Kim CJ;Tarca AL;Papp Z;Bohn H
母体-胎儿免疫耐受的失调是导致先兆子痫的机制之一。半乳糖凝集素是脊椎动物免疫反应和哺乳动物母胎免疫耐受的关键调节蛋白。先前我们发现，在灵长类进化过程中，人类胎盘半乳糖凝集素-13 （PP13）、半乳糖凝集素-14和半乳糖凝集素-16的Chr19基因簇中有三个基因出现，并可能赋予半异体胎儿免疫耐受能力。本研究涉及多种方法，包括基因和蛋白质表达谱分析、基因组DNA甲基化分析、分化滋养层细胞的功能分析，包括基因沉默、荧光素酶报告基因和甲基化分析。这些方法适用于胎盘标本、脐带血细胞、原代滋养细胞和BeWo细胞。基因组DNA序列分析转座因子、转录因子结合位点和进化保守性。在滋养细胞融合分化过程中，绒毛胎盘发育的关键转录因子介导了DNA甲基化和Chr19聚集性凝集素基因在绒毛滋养细胞中的表达。后一种机制是通过启动子进化和类人猿特异性L1PREC2转座元件插入祖先基因的5 '未翻译区，随后发生基因复制事件，从而共同选择这些转录因子的结合位点。在胎盘Chr19聚集素基因中，LGALS13和LGALS14在SGA相关的早产儿重度子痫前期表达下调。我们发现这种现象部分源于控制滋养层功能和凝集素基因表达的关键转录因子的表达失调。此外，这些基因的差异DNA甲基化也被观察到在早产子痫前期，与SGA无关。这些发现揭示了Chr19聚集素胎盘表达的进化起源。这些基因在子痫前期的复杂失调可能改变母体-胎儿界面的免疫耐受机制。
The dysregulation of maternal-fetal immune tolerance is one of the proposed mechanisms leading to preeclampsia. Galectins are key regulator proteins of the immune response in vertebrates and maternal-fetal immune tolerance in eutherian mammals. Previously we found that three genes in a Chr19 cluster encoding for human placental galectin-13 (PP13), galectin-14 and galectin-16 emerged during primate evolution and may confer immune tolerance to the semi-allogeneic fetus. This study involved various methodologies for gene and protein expression profiling, genomic DNA methylation analyses, functional assays on differentiating trophoblasts including gene silencing, luciferase reporter and methylation assays. These methods were applied on placental specimens, umbilical cord blood cells, primary trophoblasts and BeWo cells. Genomic DNA sequences were analyzed for transposable elements, transcription factor binding sites and evolutionary conservation. The villous trophoblastic expression of Chr19 cluster galectin genes is developmentally regulated by DNA methylation and induced by key transcription factors of villous placental development during trophoblast fusion and differentiation. This latter mechanism arose via the co-option of binding sites for these transcription factors through promoter evolution and the insertion of an anthropoid-specific L1PREC2 transposable element into the 5’ untranslated region of an ancestral gene followed by gene duplication events. Among placental Chr19 cluster galectin genes, the expression of LGALS13 and LGALS14 is down-regulated in preterm severe preeclampsia associated with SGA. We reveal that this phenomenon is partly originated from the dysregulated expression of key transcription factors controlling trophoblastic functions and galectin gene expression. In addition, the differential DNA methylation of these genes was also observed in preterm preeclampsia irrespective of SGA. These findings reveal the evolutionary origins of the placental expression of Chr19 cluster galectins. The complex dysregulation of these genes in preeclampsia may alter immune tolerance mechanisms at the maternal-fetal interface.