a Key Laboratory of High Magnetic Field and Ion Beam Physical Biology , Hefei Institutes of Physical Science, Chinese Academy of Sciences , Hefei , Anhui , People's Republic of China.
c Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province , Hefei , Anhui , People's Republic of China.
Nanotoxicology. 2018 Mar;12(2):117-137. doi: 10.1080/17435390.2018.1425498. Epub 2018 Jan 16.
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-NH), 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.
为了拓展工程纳米材料（如氧化石墨烯，GO）的应用，有必要将其细胞毒性降至最低。然而，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于阐明基因表达的分子基础，这为阐明与表观遗传调控相关的复杂生物学过程提供了一种更敏感和先进的技术。在这项研究中，研究了 GO 引发的染色质相互作用在正常人类细胞中激活cox2（炎症的标志）的作用。使用染色体构象捕获技术，我们表明 GO 通过 p65 和 p300 复合物介导的动态染色质环化，在人胚肾 293T（293T）细胞中引发下游增强子与 cox2 启动子之间的物理相互作用，这对于 cox2 的高表达是必需的。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参与了 cox2 激活的调节。与原始 GO 和氨基化 GO（GO-NH）相比，聚丙烯酸功能化 GO（GO-PAA）引起的炎症反应较弱，对染色质结构的影响也较弱。我们的研究结果从机制上把 GO 介导的染色质相互作用与 cox2 的调控联系起来，并表明 GO 衍生物在实际应用中可能会降低毒性。
