Fig. 5.

Working model. (A) Overexpression of N1ICD, working through RBP-Jκ, inhibits P4 signaling and overactivates E2 signaling. Dysregulation of P4 and E2 signaling contributes to implantation and decidualization failure and further leads to defective uterine receptivity as a consequence of the altered expression of their target genes. Overactivation of canonical Notch signaling decreases Pgr through hypermethylation of exon 1 by the PU.1/Dnmt3b complex. (B) The PU.1/Dnmt3b spatial working model. PU.1 first binds on the promoter of Pgr and then recruits Dnmt3b through their direct interaction. Dnmt3b binds to the CpG island from 1.3 kb away from the PU.1 binding site through a looped DNA structure and hypermethylates this region.