子宫内膜异位症(内异症)患者卵泡氧化应激水平(ROS)异常升高，但与内异症不孕的作用机制不明确。EZH2介导的组蛋白修饰是目前的研究热点，我们发现内异症患者颗粒细胞EZH2表达低于对照，且细胞ROS可下调EZH2、降低组蛋白甲基化；通过CHIP-Seq和RNA-Seq，发现IGFBP4可能是EZH2的靶基因，且IGFBP4在患者颗粒细胞异常升高。据报道，IGFBP4下调激活的IGFs可抑制卵泡闭锁、介导优势卵泡选择，且IGFs本身也具有抗氧化作用。我们提出：内异症患者卵巢颗粒细胞ROS抑制EZH2，靶向调控IGFBP4并提高其转录，引起卵泡IGF信号不足，降低细胞抗氧化作用，正反馈提高ROS水平，或将通过影响卵泡发育参与内异症不孕。课题拟结合分子生物学、动物模型与转基因小鼠、临床数据分析等手段，探讨EZH2/IGFBP4/IGFs轴对卵巢ROS水平的作用机制，为疾病综合防治提供理论基础。

Reactive oxygen species (ROS) in ovarian follicles of patients with endometriosis is abnormally elevated, but its role and mechanism in the endometriotic-associated subfertility is not clear. Recently EZH2-mediated histone modification is one of the research hotspot in physiological and pathological processes. Previously, we found that EZH2 expression levels in granulosa cells from patients with endometriosis is lower than those from controls. Hydrogen peroxide induced ROS could downregulate EZH2 and reduce the total level of cellular histone methylation on genomic DNA. Through CHIP-Seq and RNA-Seq, we found that IGFBP4 may be one of the target genes of EZH2. And IGFBP4 is abnormally elevated in granulosa cells from patients with endometriosis. As reported, downregulation of IGFBP4 and the subsequent activation of IGFs inhibits follicular atresia and mediate dominant follicular selection. Moreover, IGFs itself has antioxidant effect. Herein, we propose that in ovarian granulosa cells, ROS inhibits EZH2 expression, targeting IGFBP4 and promoting its transcription, subsequently resulting in inactivation IGF signal in follicles. Downregulation of IGF signal reduces the antioxidant effect of cells, which stimulated cells’ response and raised ROS level by positive feedback. The function and mechanism of ROS regulated by EZH2 and IGFBP4 may participate in follicular development and associate with subfertility of endometriosis. Our project aims to explore the mechanism of EZH2/IGFBP4/IGFs axis on the regulation of ROS level in ovarian granulosa cells, by investigation with molecular biological, animal models, transgenic mice and association analysis of clinical data. We believe our study will improve the theoretical understanding of endometriotic associated infertility and also benefit for prevention and treatment of the disease.