Selective Disruption of ERα DNA-Binding Activity Alters Uterine Responsiveness to Estradiol

In vitro models have been used to demonstrate that estrogen receptors (ERs) can regulate estrogen-responsive genes either by directly interacting with estrogen-responsive element (ERE) DNA motifs or by interacting with other transcription factors such as AP1. In this study, we evaluated estrogen (E-2)-dependent uterine gene profiles by microarray in the KIKO mouse, an in vivo knock-in mouse model that lacks the DNA-binding function of ER alpha and is consequently restricted to non-ERE-mediated responses. The 2- or 24-h E-2-mediated uterine gene responses were distinct in wild-type (WT), KIKO, and alpha ERKO genotypes, indicating that unique sets of genes are regulated by ERE and non-ERE pathways. After 2 h E-2 treatment, 38% of the WT transcripts were also regulated in the KIKO, demonstrating that the tethered mechanism does operate in this in vivo model. Surprisingly, 1438 E-2-regulated transcripts were unique in the KIKO mouse and were not seen in either WT or alpha ERKO. Pathway analyses revealed that some canonical pathways, such as the Jak/Stat pathway, were affected in a similar manner by E-2 in WT and KIKO. In other cases, however, the WT and KIKO differed. One example is the Wnt/beta-catenin pathway; this pathway was impacted, but different members of the pathway were regulated by E-2 or were regulated in a different manner, consistent with differences in biological responses. In summary, this study provides a comprehensive analysis of uterine genes regulated by E-2 via ERE and non-ERE pathways. (Molecular Endocrinology 23: 2111-2116, 2009)