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首页> 外文期刊>Epigenetics: official journal of the DNA Methylation Society >Rapid and specific hypomethylation of enhancers in endothelial cells during adaptation to cell culturing
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Rapid and specific hypomethylation of enhancers in endothelial cells during adaptation to cell culturing

机译：在适应细胞培养过程中内皮细胞中增强子的快速和特异性低甲基化

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Epigenetics, including DNA methylation, is one way for a cell to respond to the surrounding environment. Traditionally, DNA methylation has been perceived as a quite stable modification; however, lately, there have been reports of a more dynamic CpG methylation that can be affected by, for example, long-term culturing. We recently reported that methylation in the enhancer of the gene encoding the key fibrinolytic enzyme tissue-type plasminogen activator (t-PA) was rapidly erased during cell culturing. In the present study we used sub-culturing of human umbilical vein endothelial cells (HUVECs) as a model of environmental challenge to examine how fast genome-wide methylation changes can arise. To assess genome-wide DNA methylation, the Infinium HumanMethylation450 BeadChip was used on primary, passage 0, and passage 4 HUVECs. Almost 2% of the analyzed sites changed methylation status to passage 4, predominantly displaying hypomethylation. Sites annotated as enhancers were overrepresented among the differentially methylated sites (DMSs). We further showed that half of the corresponding genes concomitantly altered their expression, most of them increasing in expression. Interestingly, the stroke-related gene HDAC9 increased its expression several hundredfold. This study reveals a rapid hypomethylation of CpG sites in enhancer elements during the early stages of cell culturing. As many methods for methylation analysis are biased toward CpG rich promoter regions, we suggest that such methods may not always be appropriate for the study of methylation dynamics. In addition, we found that significant changes in expression arose in genes with enhancer DMSs. HDAC9 displayed the most prominent increase in expression, indicating, for the first time, that dynamic enhancer methylation may be central in regulating this important stroke-associated gene.
机译：表观遗传学，包括DNA甲基化，是细胞对周围环境做出反应的一种方式。传统上，DNA甲基化被认为是相当稳定的修饰。但是，最近有报道说，动态CpG甲基化可能受到例如长期培养的影响。我们最近报道，在细胞培养过程中，编码关键纤溶酶组织型纤溶酶原激活物（t-PA）的基因的增强子中的甲基化被迅速消除。在本研究中，我们使用人类脐静脉内皮细胞（HUVEC）的亚培养作为环境挑战的模型，以检验全基因组范围内甲基化变化的发生速度。为了评估全基因组DNA甲基化，在主要，第0代和第4代HUVEC上使用了Infinium HumanMethylation450 BeadChip。几乎2％的分析位点将甲基化状态更改为第4代，主要显示甲基化不足。在差异甲基化位点（DMS）中，标注为增强子的位点过多。我们进一步表明，相应基因的一半同时改变了它们的表达，其中大多数表达增加了。有趣的是，中风相关基因HDAC9将其表达提高了数百倍。这项研究揭示了在细胞培养的早期阶段，增强子元件中CpG位点的快速低甲基化。由于许多甲基化分析方法偏向富含CpG的启动子区域，因此我们建议此类方法可能并不总是适合于甲基化动力学研究。另外，我们发现在具有增强子DMS的基因中表达发生了显着变化。 HDAC9表现出最突出的表达增加，这首次表明动态增强子甲基化可能是调节这一重要的中风相关基因的关键。

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