UCA1通过DNA甲基化及组蛋白乙酰化修饰激活NRF2调控的抗氧化系统拮抗皮肤光老化的机制研究

NRF2调控的抗氧化系统在拮抗皮肤光老化中起关键作用，但具体调控机制不清。前期研究发现：lncRNA UCA1在光老化皮肤中与NRF2的表达呈正相关；过表达UCA1能上调角质形成细胞和成纤维细胞中NRF2的表达，且能拮抗UVB诱导的细胞衰老及ROS。因此UCA1极可能通过激活NRF2-抗氧化系统拮抗皮肤光老化。研究报道NRF2受到DNA甲基化及组蛋白乙酰化修饰的调控。预实验发现在角质形成细胞和成纤维细胞中过表达UCA1后，NRF2启动子的DNA甲基化水平降低，但H3K27ac水平增高。因此，我们提出“UCA1通过调控DNA甲基化及H3K27ac激活NRF2-抗氧化系统拮抗皮肤光老化”的假说。本研究将从细胞、动物及临床水平验证UCA1通过激活NRF2-抗氧化系统拮抗皮肤光老化的作用，并探索UCA1调控DNA甲基化及H3K27ac激活NRF2表达及功能的具体机制，为皮肤光老化的防治提供新方向。

The antioxidant system regulated by NRF2 plays a key role in antagonizing skin photoaging, but the specific regulatory mechanism is unclear. Previous studies found that there is a positive correlation between the expression of lncRNA UCA1 and NRF2 in photoaging skin, and overexpression of UCA1 could up-regulate the expression of NRF2 in keratinocytes and fibroblasts, then antagonize cellular ROS and photoaging induced by UVB. Therefore, UCA1 may antagonize skin photoaging by activating NRF2- antioxidant system. It has been reported that NRF2 is regulated by DNA methylation and histone acetylation. Preliminary experiment showed that while overexpressed UCA1 in keratinocytes and fibroblasts, the level of DNA methylation of NRF2 promoter decreased, but the level of H3K27ac increased. Therefore, we propose the hypothesis that UCA1 antagonizes skin photoaging by regulating DNA methylation and H3K27ac, then activates NRF2- antioxidant system. In this study, we will verify the antagonistic effect of UCA1 on skin photoaging by activating NRF2- antioxidant system at cellular, animal and clinical levels, and reveal the specific mechanism of UCA1 activating NRF2 expression and function via regulating DNA methylation and H3K27ac, so as to provide a new area for the prevention and treatment of skin photoaging.