Fig. 8.

Proposed model for KLF4 and KLF15 mediation of E₂ and P₄E₂ action in the uterine epithelium. In E₂ exposed uterine epithelial cells, KLF4 binds to the MCM2 promoter and promotes histone demethylation and acetylation with the concomitant binding of RNA Pol II and transcription of the Mcm2 gene. This increased mRNA level leads to MCM protein accumulation and the assembly of the prereplication complex with the resultant DNA synthesis. In contrast, P₄E₂ treatment stimulates KLF15 and inhibits KLF4 epithelial cell expression. KLF15 in turn binds to the Mcm2 promoter and recruits HDACs that deacetylates the histones on the promoter. This deacetylation together with increased DNA methylation results in loss of RNA Pol II binding and suppression of Mcm2 transcription. Consequently, MCM2 levels are reduced in the cell, the binding of the hexameric MCM complex to the origins of DNA replication is blocked, and DNA synthesis is inhibited.