Konyushatova Аlina О, Deryabin Pavel I, Melnik Anastasia P, Daks Aleksandra A, Borodkina Aleksandra V
Mechanisms of Cellular Senescence Laboratory, Institute of Cytology of the Russian Academy of Sciences, Saint-Petersburg, Russia.
Gene Expression Regulation Laboratory, Institute of Cytology of the Russian Academy of Sciences, Saint-Petersburg, Russia.
Mol Hum Reprod. 2025 Apr 3;31(2). doi: 10.1093/molehr/gaaf028.
Stepwise decidualization of endometrial stromal cells (EnSC) mediates the ability of the endometrium to respond to embryo quality, determining whether to permit or restrict its implantation. Currently, epigenetic mechanisms are recognized as key regulators of transcriptional gene networks during this hormone-induced differentiation of EnSC. In this study, we focused on the potential role of histone methyltransferase SETD7 in regulating EnSC decidualization. Using SETD7 knockout EnSC, we demonstrated that SETD7 is essential for proper decidualization; however, its impact is rather associated with stabilization of the estrogen receptor protein than with its histone methylation activity. By analyzing publicly available single-cell RNA sequencing data, we found that activation of SETD7 expression precedes the emergence of decidual subpopulations during EnSC decidualization. Furthermore, we identified SETD7 as a critical regulator of cell fate divergence of decidualizing EnSC, as cells lacking SETD7 expression exhibit accelerated senescence and an impaired decidual response. Finally, through the combined analysis of the available single-cell RNA sequencing data and the bulk mRNA microarray data for endometrial tissue, we revealed lower levels of SETD7 expression in patients with recurrent pregnancy losses. This decrease in SEDT7 expression correlates well with a reduced ratio of SCARA5/DIO2 gene expression in the endometrial stroma of these patients. Our data uncover SETD7 as a novel molecular regulator of EnSC decidualization, required for the proper establishment of decidual subpopulations.
子宫内膜基质细胞（EnSC）的逐步蜕膜化介导了子宫内膜对胚胎质量作出反应的能力，决定是允许还是限制胚胎着床。目前，表观遗传机制被认为是在EnSC这种激素诱导分化过程中转录基因网络的关键调节因子。在本研究中，我们聚焦于组蛋白甲基转移酶SETD7在调节EnSC蜕膜化中的潜在作用。利用SETD7基因敲除的EnSC，我们证明SETD7对于正常蜕膜化至关重要；然而，其影响与其说是与组蛋白甲基化活性相关，不如说是与雌激素受体蛋白的稳定有关。通过分析公开的单细胞RNA测序数据，我们发现SETD7表达的激活在EnSC蜕膜化过程中蜕膜亚群出现之前。此外，我们确定SETD7是蜕膜化EnSC细胞命运分化的关键调节因子，因为缺乏SETD7表达的细胞表现出加速衰老和蜕膜反应受损。最后，通过对子宫内膜组织的现有单细胞RNA测序数据和大量mRNA微阵列数据的综合分析，我们发现复发性流产患者中SETD7表达水平较低。这些患者子宫内膜基质中SETD7表达的降低与SCARA5/DIO2基因表达比例的降低密切相关。我们的数据揭示SETD7是EnSC蜕膜化的一种新型分子调节因子，是正常建立蜕膜亚群所必需的。
