Endometrial aging is accompanied by H3K27ac and PGR loss
Yue Wang, Ping Zhou, Hongying Shan, Xiyao Liu, Ming Cheng, Zhenhong Ye, Xiunan Chen, Baoying Liao, Tianliu Peng, Chenxi Xiao, Ziying Huang, Yunshu Dong, Yang Yu, Heng Pan, Rong Li
Abstract
Whether and how endometrial aging affects fertility remains unclear. In our in-house clinical cohort at the Center for Reproductive Medicine of Peking University Third Hospital (n = 1,149), we observed adverse pregnancy outcomes in the middle-aged group after excluding aneuploid embryos, implying the negative impact of endometrial aging on fertility. To understand endometrial aging, we performed comprehensive transcriptomic profiling of the mid-secretory endometrium of young (<35 years) and middle-aged (≥35 years) patients. This analysis revealed that H3K27ac loss is linked to impaired endometrial receptivity in the middle-aged group. We eliminated H3K27ac in young human endometrial stromal cells and observed reduced progesterone receptor (PGR), a critical regulator of endometrial receptivity. Lastly, we validated the association between H3K27ac/PGR loss and uterine aging in a mouse model. Our findings establish H3K27ac as a critical regulator of PGR and demonstrate that endometrial H3K27ac loss is associated with aging-related fertility decline. This work provides valuable insights into enhancing the safety and efficacy of assisted reproductive technologies in future clinical practices. Implantation of the embryo into the endometrium is critical for fertility; however, how endometrial aging impacts pregnancy outcomes is incompletely understood. Here the authors identify, in a cohort of patients undergoing pre-implantation genetic testing for aneuploidy, H3K27ac loss as a hallmark of endometrial aging, affecting endometrial receptivity in both PGR-dependent and PGR-independent manners.