The Exploration Of The PR-Set7's Function During The Uterine Stromal Development In Mice

As the increasing incidence of infertility,the development of individuals,families and even society has been greatly affected.Reproductive health has become the focus of national attention.Therefore,its pathogenesis and clinical treatment have become the primary task of reproductive medicine researchers.A normal-developed endometrial stroma is one of the primary conditions for the establishment of uterine receptive state,while its dysplasia directly leads to failure of embryo implantation and subsequent pregnancy.PR-Set7,a sole lysine methyltransferase that catalyzes monomethylation of histone H4 lysine 20(H4K20mel),has been well characterized in a variety of biological processes.In view of its key role in early embryonic development and organ development,it is speculated that it is involved in endometrial development,but the exact role and specific mechanism have not been clarified.The complexity of the endometrial stromal development has always been a huge challenge,become a hotspot in research of reproductive medicine with difficulty.In this study,we observed that PR-Set7 was highly expressed in the uterus of the postnatal mouse,and the conditional k:nockout mice established by PR-Cre were significantly thinner and developed abnormally.Subsequent analysis revealed that uterine PR-Set7 deficiency restricted stromal cell growth on postnatal day 15.The deletion of Set7 caused abnormal changes of Cyclin E1 and its inhibiting factor P21 by significantly down-regulating H4K20me1.The transition of the cell from G1 phase to S phase failed.BrdU incorporation,that is,DNA replication is substantially reduced.At the same time,by treating primary uterine stromal cells with inhibitors,we further confirmed its regulatory effect on DNA replication of uterine stromal cells in vitro.Moreover,we further revealed that it regulates the recruitment of DNA helicases MCM2/6 to chromatin through the epigenetic regulation mediated by H4K20me1,establishes the replication license and initiates DNA replication,which regulate the development of endometrial stroma.Our study revealed for the first time the key role of histone methyltransferase PR-Set7 in the DNA replication process of endometrial stromal cells through h4k20me-mediated epigenetic regulation,suggesting that epigenetic modification regulation should also be paid attention to in clinical diagnosis of infertility besides eliminating congenital genomic defects.In addition,it also has reference significance for the periodic endometrial renewal of adult women,that is,endometrial repair after shedding during menstruation.