SOX4 facilitates PGR protein stability and FOXO1 expression conducive for human endometrial decidualization.
SOX4 facilitates PGR protein stability and FOXO1 expression conducive for human endometrial decidualization.
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作者：
Huang P;Deng W;Bao H;Lin Z;Liu M;Wu J;Zhou X;Qiao M;Yang Y;Cai H;Rao F;Chen J;Chen D;Lu J;Wang H;Qin A;Kong S
人类妊娠的建立需要间质细胞的适当蜕膜化，这涉及到月经周期内子宫内膜间质细胞在类固醇调控下的周期性转化。然而，人类蜕膜化启动和维持的潜在分子调控机制尚未完全阐明。在这项研究中，我们证明了Sox4是人子宫内膜间质细胞蜕膜化的关键调节因子，通过直接调节FOXO1的表达，通过Sox4全基因组结合和RNA测序揭示了这一点。此外，我们的免疫沉淀和质谱学结果揭示，Sox4通过抑制E3泛素连接酶HERC4介导的降解来调节孕酮受体(PGR)的稳定性。更重要的是，我们提供的证据表明，在体外受精(IVF)患者中，SOX4-HERC4-PGR轴的异常调节是导致蜕膜功能缺陷和再植入失败的潜在原因。综上所述，本研究证明Sox4是人类子宫内膜蜕膜化的一个新的关键调节因子，为蜕膜化相关不孕症的发病机制提供了有洞察力的信息，并将为改善妊娠状态铺平道路。
The establishment of pregnancy in human necessitates appropriate decidualization of stromal cells, which involves steroids regulated periodic transformation of endometrial stromal cells during the menstrual cycle. However, the potential molecular regulatory mechanism underlying the initiation and maintenance of decidualization in humans is yet to be fully elucidated. In this investigation, we document that SOX4 is a key regulator of human endometrial stromal cells decidualization by directly regulating FOXO1 expression as revealed by whole genomic binding of SOX4 assay and RNA sequencing. Besides, our immunoprecipitation and mass spectrometry results unravel that SOX4 modulates progesterone receptor (PGR) stability through repressing E3 ubiquitin ligase HERC4-mediated degradation. More importantly, we provide evidence that dysregulated SOX4–HERC4–PGR axis is a potential cause of defective decidualization and recurrent implantation failure in in-vitro fertilization (IVF) patients. In summary, this study evidences that SOX4 is a new and critical regulator for human endometrial decidualization, and provides insightful information for the pathology of decidualization-related infertility and will pave the way for pregnancy improvement.