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.

中文翻译：

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子宫内膜上皮 ARID1A 对于早期妊娠建立中的子宫腺功能至关重要


尽管子宫内膜异位症和不孕症明显相关，但其病理生理机制仍不清楚。先前的工作已将子宫内膜 ARID1A 缺失与子宫内膜异位症相关的子宫内膜不接受性联系起来。在这里，我们在小鼠中证明 ARID1A 结合并调节子宫内膜腺功能所需的 Foxa2 基因的转录。子宫特异性缺失 Arid1a 会损害腺体发育并减少 Foxa2 和 Lif 的表达。在成年小鼠子宫内膜上皮中用 Ltf-iCre 删除 Arid1a 可保留腺体发育，但仍会损害腺体功能。缺乏子宫内膜上皮 Arid1a 的小鼠由于 LIF-STAT3-EGR1 通路破坏导致着床、蜕膜化和子宫内膜容受性缺陷而严重生育力低下。患有子宫内膜异位症的女性子宫内膜中的 FOXA2 也减少，这与 ARID1A 的减少相关，并且在子宫内膜异位症诱导的非人灵长类动物中，ARID1A 和 FOXA2 均减少。我们的研究结果描述了 ARID1A 在子宫内膜上皮中通过维持腺体功能支持早期妊娠建立的作用。