To extend the applications of engineered nanomaterials, such as graphene oxide (GO), it is necessary to minimize cytotoxicity. However, the mechanisms underlying this cytotoxicity are unclear. Dynamic chromosomal interactions have been used to illustrate the molecular bases of gene expression, which offers a more sensitive and cutting-edge technology to elucidate complex biological processes associated with epigenetic regulations. In this study, the role of GO-triggered chromatin interactions in the activation of cox2, a hallmark of inflammation, was investigated in normal human cells. Using chromosome conformation capture technology, we showed that GO triggers physical interactions between the downstream enhancer and the cox2 promoter in human embryonic kidney 293T (293T) via p65 and p300 complex-mediated dynamic chromatin looping, which was required for high cox2 expression. Moreover, tumor necrosis factor-α (TNF-α), located upstream of the p65 signaling pathway, contributed to the regulation of cox2 activation through dynamic chromatin architecture. Compared with pristine GO and aminated GO (GO-NH₂), poly (acrylic acid)-functionalized GO (GO-PAA) induced a weaker inflammatory response and a weaker effect on chromatin architecture. Our results mechanistically link GO-mediated chromatin interactions with the regulation of cox2 and suggest that GO derivatives may minimize toxicity in practical applications.

中文翻译：

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氧化石墨烯通过表观遗传机制调控人类胚胎肾脏293T细胞中的cox2：动态染色体相互作用

为了扩展工程化的纳米材料的应用，例如氧化石墨烯（GO），有必要将细胞毒性降至最低。但是，这种细胞毒性的机制尚不清楚。动态染色体相互作用已被用来说明基因表达的分子基础，它提供了一种更灵敏，最前沿的技术来阐明与表观遗传调控相关的复杂生物过程。在这项研究中，在正常人细胞中研究了GO触发的染色质相互作用在激活cox2（炎症的标志）中的作用。使用染色体构象捕获技术，我们表明GO触发了下游增强子与cox2之间的物理相互作用p65和p300复合物介导的动态染色质环化在人类胚胎肾脏293T（293T）中启动子启动子，这是高cox2表达所必需的。此外，位于p65信号通路上游的肿瘤坏死因子-α（TNF-α）通过动态染色质结构促进了cox2激活的调节。与原始GO和胺化GO（GO-NH ₂）相比，聚丙烯酸功能化GO（GO-PAA）引起较弱的炎症反应，对染色质结构的影响也较弱。我们的研究结果将GO介导的染色质相互作用与cox2的调节机制联系起来，表明GO衍生物可以在实际应用中将毒性降至最低。