Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI, USA.
Cell and Molecular Biology Program, Michigan State University, East Lansing, MI, USA.
FASEB J. 2021 Feb;35(2):e21209. doi: 10.1096/fj.202002178R. Epub 2020 Nov 22.
Though endometriosis and infertility are clearly associated, the pathophysiological mechanism remains unclear. Previous work has linked endometrial ARID1A loss to endometriosis-related endometrial non-receptivity. Here, we show in mice that ARID1A binds and regulates transcription of the Foxa2 gene required for endometrial gland function. Uterine-specific deletion of Arid1a compromises gland development and diminishes Foxa2 and Lif expression. Deletion of Arid1a with Ltf-iCre in the adult mouse endometrial epithelium preserves the gland development while still compromising the gland function. Mice lacking endometrial epithelial Arid1a are severely sub-fertile due to defects in implantation, decidualization, and endometrial receptivity from disruption of the LIF-STAT3-EGR1 pathway. FOXA2 is also reduced in the endometrium of women with endometriosis in correlation with diminished ARID1A, and both ARID1A and FOXA2 are reduced in nonhuman primates induced with endometriosis. Our findings describe a role for ARID1A in the endometrial epithelium supporting early pregnancy establishment through the maintenance of gland function.
虽然子宫内膜异位症和不孕显然相关，但病理生理机制仍不清楚。先前的工作将子宫内膜 ARID1A 的缺失与与子宫内膜异位症相关的子宫内膜无反应性联系起来。在这里，我们在小鼠中表明，ARID1A 结合并调节 Foxa2 基因的转录，Foxa2 基因是子宫内膜腺功能所必需的。ARID1A 的子宫特异性缺失会损害腺的发育，并降低 Foxa2 和 Lif 的表达。在成年小鼠子宫内膜上皮细胞中使用 Ltf-iCre 删除 Arid1a 会保留腺的发育，同时仍然损害腺的功能。由于植入、蜕膜化和子宫内膜容受性的缺陷，破坏了 LIF-STAT3-EGR1 途径，缺乏子宫内膜上皮细胞 ARID1A 的小鼠由于植入失败而严重不孕。FOXA2 在子宫内膜异位症患者的子宫内膜中也减少，与 ARID1A 的减少相关，在诱导子宫内膜异位症的非人类灵长类动物中，ARID1A 和 FOXA2 均减少。我们的研究结果描述了 ARID1A 在支持早期妊娠建立的子宫内膜上皮细胞中的作用，通过维持腺的功能。
