The majority of the biological effects of estrogens in the reproductive tract are mediated by estrogen receptor , which regulates transcription by several mechanisms. As the tissue-specific effects of some ER ligands may be caused by tissue-specific transcriptional mechanisms of ER we aimed to identify the contribution of DNA recognition to these mechanisms in two clinically important target organs, namely uterus and liver.

We used a genetic mouse model that dissects DNA binding-dependent versus independent transcriptional regulation elicited by ER. The EAAE mutant harbors amino acid exchanges at four positions of the DNA binding domain of ER. This construct was knocked in the ER gene locus to produce ER_(EAAE/EAAE) mice devoid of a functional ER DNA binding domain. The phenotype of the ER_(EAAE/EAAE) mice resembles the general loss-of-function phenotype of ERKO mutant mice with hypoplastic uteri, hemorrhagic ovaries, and impaired mammary gland development. In agreement with this phenotype, the expression pattern of the ER_(EAAE/EAAE) mutant mice in liver obtained by genome-wide gene expression profiling supports the observation of a near-complete loss of estrogen-dependent gene regulation in comparison to the wild-type. Further gene expression analyses to validate the results of the microarray data were performed by qRT-PCR. The analyses indicate that both gene activation and repression by estrogen-bound ER relies on an intact DNA binding domain in vivo.