Endometrial epithelial ARID1A is critical for uterine gland function in early pregnancy establishment.
Endometrial epithelial ARID1A is critical for uterine gland function in early pregnancy establishment.
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子宫内膜上皮ARID1A对于妊娠早期建立过程中的子宫腺功能至关重要。
DOI：
10.1096/fj.202002178r
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Jeong JW
中科院分区：
文献类型：
--
作者：
Marquardt RM;Kim TH;Yoo JY;Teasley HE;Fazleabas AT;Young SL;Lessey BA;Arora R;Jeong JW
虽然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。先前的工作已经将子宫内膜ARID 1A损失与子宫内膜异位症相关的子宫内膜非容受性联系起来。在这里，我们在小鼠中显示，ARID 1A结合并调节子宫内膜腺体功能所需的Foxa 2基因的转录。子宫特异性缺失Arid 1a损害腺体发育并减少Foxa 2和Lif表达。成年小鼠子宫内膜上皮中用Ltf-iCre缺失Arid 1a可以保留腺体发育，同时仍然损害腺体功能。缺乏子宫内膜上皮Arid 1a的小鼠由于LIF-STAT 3-EGR 1通路的破坏而导致着床、蜕膜化和子宫内膜容受性的缺陷而严重生育力低下。FOXA 2在患有子宫内膜异位症的女性的子宫内膜中也减少，与减少的ARID 1A相关，并且ARID 1A和FOXA 2在子宫内膜异位症诱导的非人灵长类动物中减少。我们的研究结果描述了ARID 1A在子宫内膜上皮中的作用，通过维持腺体功能来支持早期妊娠的建立。
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 gland development while still compromising 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 non-human 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.