Novakovic Boris, Evain-Brion Danièle, Murthi Padma, Fournier Thiery, Saffery Richard
Cancer and Disease Epigenetics, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
FASEB J. 2017 Jun;31(6):2380-2392. doi: 10.1096/fj.201601189RR. Epub 2017 Feb 21.
Placental functioning relies on the appropriate differentiation of progenitor villous cytotrophoblasts (CTBs) into extravillous cytotrophoblasts (EVCTs), including invasive EVCTs, and the multinucleated syncytiotrophoblast (ST) layer. This is accompanied by a general move away from a proliferative, immature phenotype. Genome-scale expression studies have provided valuable insight into genes that are associated with the shift to both an invasive EVCT and ST phenotype, whereas genome-scale DNA methylation analysis has shown that differentiation to ST involves widespread methylation shifts, which are counteracted by low oxygen. In the current study, we sought to identify DNA methylation variation that is associated with transition from CTB to ST and from a noninvasive to invasive EVCT phenotype after culture on Matrigel. Of the several hundred differentially methylated regions that were identified in each comparison, the majority showed a loss of methylation with differentiation. This included a large differentially methylated region (DMR) in the gene body of death domain-associated protein 6 ( ), which lost methylation during both CTB syncytialization to ST and EVCT differentiation to invasive EVCT. Comparison to publicly available methylation array data identified the same DMR as among the most consistently differentially methylated genes in placental samples from preeclampsia pregnancies. Of interest, culture of CTB or ST in low oxygen increases methylation in the same region, which correlates with delayed differentiation. Analysis of combined epigenomics signatures confirmed DMR as a likely regulatory element, and direct gene expression analysis identified a positive association between methylation at this site and expression levels. The widespread dynamic nature of methylation in association with trophoblast differentiation and placenta-associated pathologies is consistent with an important role for this gene in proper placental development and function.-Novakovic, B., Evain-Brion, D., Murthi, P., Fournier, T., Saffery, R. Variable DAXX gene methylation is a common feature of placental trophoblast differentiation, preeclampsia, and response to hypoxia.
胎盘功能依赖于绒毛前体细胞滋养层细胞（CTBs）向绒毛外滋养层细胞（EVCTs）的适当分化，包括侵袭性EVCTs，以及多核合体滋养层（ST）层。这伴随着从增殖性、未成熟表型的总体转变。全基因组表达研究为与向侵袭性EVCT和ST表型转变相关的基因提供了有价值的见解，而全基因组DNA甲基化分析表明，向ST的分化涉及广泛的甲基化变化，低氧可抵消这种变化。在本研究中，我们试图确定在基质胶上培养后与CTB向ST以及从非侵袭性向侵袭性EVCT表型转变相关的DNA甲基化变异。在每次比较中鉴定出的数百个差异甲基化区域中，大多数显示随着分化甲基化缺失。这包括死亡结构域相关蛋白6（ ）基因体内的一个大的差异甲基化区域（DMR），在CTB向ST合体化以及EVCT向侵袭性EVCT分化过程中该区域均失去甲基化。与公开可用的甲基化阵列数据比较发现，同一DMR是子痫前期妊娠胎盘样本中最一致差异甲基化基因之一。有趣的是，在低氧条件下培养CTB或ST会增加同一区域的甲基化，这与分化延迟相关。对联合表观基因组特征的分析证实该DMR可能是一个调控元件，直接基因表达分析确定该位点的甲基化与 表达水平呈正相关。与滋养层分化和胎盘相关病理相关的 甲基化广泛动态性质与该基因在正常胎盘发育和功能中的重要作用一致。-诺瓦科维奇，B.，埃万 - 布里昂，D.，穆尔蒂，P.，富尔尼耶，T.，萨费里，R. 可变的DAXX基因甲基化是胎盘滋养层分化、子痫前期及对缺氧反应的共同特征
