Chromatin remodeling of prostaglandin signaling in smooth muscle enables mouse embryo passage through the female reproductive tract [RNA-seq]

After fertilization, early mammalian development takes place as the embryo transits the oviduct prior to implantation on the wall of the uterus. This transport is precisely orchestrated by secreted oviduct fluid, unidirectional beating of epithelial cilia and smooth muscle contractions. Using multiple gene-edited mice to affect the female reproductive tract, we document that conditional disruption of Pbrm1, a component of the SWI/SNF chromatin remodeling complex, prevents embryo transport. Loss of Pbrm1 in epithelial cells lining the oviduct had no effect, but ablation in smooth muscle phenocopied the transport defect without perturbing embryogenesis. Analysis with RNA-seq, ATAC-seq, ChIC-seq and pharmacologic rescue experiments implicated prostaglandin signaling pathways. In comparison to wildtype, gene-edited mice had compromised chromatin accessibility at enhancer/promoters of Ptgs2, Pla2g16, Pla2r1 and Ptger3 (EP3) as well as decreased enhancer-promoter interactive looping critical for Ptgs2 (prostaglandin-endoperoxide synthase 2, aka Cox-2) expression in a SWI/SNF complex dependent manner in smooth muscle. These observations provide mechanistic insight into potential causes of ectopic pregnancy in fallopian tubes that is a significant cause of morbidity and mortality in human pregnancies. Overall design: RNA-seq was performed using D2 primary oviductal smooth muscle cell between control and Pbrm1 cKO mice in order to identify the differentially expressed genes.