Selective disruption of ER{alpha} 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 ERalpha 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 alphaERKO 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 alphaERKO. 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.
Hewitt
Sylvia C
SC
National Institute of Environment Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. curtiss@niehs.nih.gov
O'Brien
Jeanne E
JE
Jameson
J Larry
JL
Kissling
Grace E
GE
Korach
Kenneth S
KS
D000818:Animals; D004247:DNA / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D010052:Ovariectomy; D017354:Point Mutation; D011485:Protein Binding / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D047628:Estrogen Receptor alpha; D004967:Estrogens; D051153:Wnt Proteins; D051176:beta Catenin; D004958:Estradiol; D004247:DNA