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. 2009 Dec;23(12):2111-6.
doi: 10.1210/me.2009-0356. Epub 2009 Oct 7.

Selective disruption of ER{alpha} DNA-binding activity alters uterine responsiveness to estradiol

Sylvia C Hewitt  1 , Jeanne E O'Brien, J Larry Jameson, Grace E Kissling, Kenneth S Korach
Affiliations

Selective disruption of ER{alpha} DNA-binding activity alters uterine responsiveness to estradiol

Sylvia C Hewitt et al. Mol Endocrinol. 2009 Dec.

Abstract

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.

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Figures

Figure 1
Figure 1
Microarray comparison of WT, KIKO, and αERKO responses to E2. Hierarchical clusters were built in Rosetta Resolver using cutoffs of P < 0.001, signal intensity of at least 100 in at least one sample, and at least 2-fold change in expression in at least one of the conditions. Each horizontal row represents comparison of saline vehicle (V) with E2 (E) for the indicated ERα genotype (WT, KIKO, or αERKO). Genes increased relative to vehicle-treated are red; decreased are green. Venn diagrams (after cutoffs of P < 0.001, signal intensity >100, and 2-fold change were applied) were also generated using Rosetta Resolver.
Figure 2
Figure 2
Selection of genes from Venn diagram analysis in Rosetta Resolver of genes regulated by E2 after 2 h that are unique to or common to WT and KIKO. Microarray data (after cutoffs of P < 0.001 and 2-fold change were applied) were displayed as Venn diagrams in Rosetta Resolver, and lists of genes uniquely regulated by E2 after 2 h in either WT or KIKO genotypes and those that were regulated in common, after removing anti-correlated transcripts, were selected and broadcast onto scatter plots of each experiment to ensure selection of genes that were significantly regulated. The lists are displayed as clusters to emphasize the unique or overlapping responses.
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