The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

The estrogen receptor mediates the effects of estrogens and antiestrogens in target cells by binding of the receptor to specific DNA sequences present in target genes. This interaction of the estrogen receptor with DNA plays a critical role in development and maintenance of reproductive, cardiovascular, neural, and skeletal cells. Although the receptor-DNA interaction is of paramount importance in the regulation of estrogen-responsive genes, the mechanism by which this interaction leads to changes in gene expression is not well understood.

Our laboratory uses in vitro and in vivo assays to examine the interaction of the estrogen receptor with DNA in order to define mechanisms involved in regulating estrogen-responsive genes. We have demonstrated that the ability of the estrogen receptor to activate transcription is related to its ability to induce directed DNA bending suggesting that DNA bending may facilitate receptor-protein contacts required for transcription activation. We have also demonstrated that the conformation of the estrogen receptor is different when bound to slightly different recognition sequences in DNA. Our findings support the idea that the estrogen receptor is comprised of a large repertoire of functional surfaces that can be formed and serve as contact points for other cellular proteins. The presentation of these functional surfaces and the selection of receptor-associated proteins, which is dictated by a unique DNA sequence, may provide the regulatory versatility required for differential expression of multiple estrogen-responsive genes in a single cell. Taken together, our studies imply that receptor-DNA interaction is a dynamic process involving conformational changes in both receptor and DNA.

Using newly developed, highly sensitive molecular biology techniques, we are examining endogenous, estrogen-responsive genes in intact human breast cancer cells to define how chromatin structure plays a role in estrogen- and antiestrogen- regulated gene transcripion. Understanding the mechanisms by which estrogen agonists and antagonists modulate gene expression is particularly important in light of the fact that these compounds are widely used in hormone replacement therapy and in breast cancer treatment and prevention.