Regulation of gene transcription by estrogen receptors alpha and beta: DNA binding, tethering, and coregulatory protein recruitment

Estrogen is a hormone of critical importance in regulating the development, growth, and maintenance of reproductive tissues. The effects of estrogen are mediated through interaction of the estrogen receptor (ER) with estrogen response elements (EREs) in target genes. Because the ER-ERE interaction plays a crucial role in gene expression, there has been great interest in understanding how this interaction leads to changes in transcription. The work detailed in this study demonstrates that ERalpha and ERbeta differ greatly in their abilities to activate transcription.; To determine whether receptor-induced changes in DNA structure are related to transactivation, the abilities of ERalpha and ERbeta to activate transcription and induce distortion and bending in DNA were compared. We have now shown that although both receptors interact with an ERE, only ERalpha is able to induce a directed change in DNA conformation, and this ERalpha-mediated change in DNA conformation enhances transcription. A number of estrogen-responsive genes, including the human progesterone receptor (PR) gene, contain no identifiable ERE. ERalpha is able to interact with DNA-bound transcription factors to induce gene transcription through a tethering mechanism. We have identified a region in the PR gene that contains two Sp1 sites and conferred estrogen responsiveness to a heterologous promoter in an estrogen and ERalpha-dependent manner. This region and three Sp1- or AP-1 site-containing regions of the PR gene were examined for ability to be activated by ERalpha or ERbeta in the presence of seven ligands in mammary, uterine, and bone cell lines. ERalpha was a more potent activator of transcription than ERbeta, and AP-1 sites were less transcriptionally active than Sp1 sites. These ERalpha and ERbeta-mediated changes in transcription require the recruitment of coregulatory proteins. We have recently identified interaction between a protein disulfide isomerase and ERalpha that results in enhancement of ERalpha-DNA interaction and ER-mediated transcription.; Combining various cis-elements and coregulatory proteins to regulate gene expression may allow for differential expression of the gene under different cell environments and physiological conditions. These studies will advance our understanding of the complex mechanisms by which ERalpha is able to regulate gene expression.