Lysine methyltransferase SETD7 coordinates the emergence of mature and senescent subpopulations during the decidualization of endometrial stromal cells.

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.