Differential modulation of DNA conformation by estrogen receptors alpha and beta

The human estrogen receptor (ER) induces transcription of estrogen-responsive genes upon binding to estrogen and the estrogen response element (ERE). To determine whether receptor-induced changes in DNA structure are related to transactivation, we compared the abilities of ER alpha and ER beta to activate transcription and induce distortion and bending in DNA. ER alpha induced higher levels of transcription than ER beta in the presence of 17 beta-estradiol. In circular permutation experiments ER alpha induced greater distortion in DNA fragments containing the consensus ERE sequence than ER beta. Phasing analysis indicated that ER alpha induced a bend directed toward the major groove of the DNA helix but that ER beta failed to induce a directed DNA bend. Likewise, the ER alpha DNA binding domain (DBD) and hinge region induced a bend directed toward the major groove of the DNA helix, but the ER beta DBD and hinge region failed to bend ERE-containing DNA fragments. Using receptor chimeras we demonstrated that the ER alpha DBD C-terminal extension is required for directed DNA bending. Transient transfection assays revealed that appropriately oriented DNA bending enhances receptor-mediated transactivation. The different abilities of ER alpha and ER beta to induce change in DNA structure could foster or inhibit the interaction of regulatory proteins with the receptor and other transcription factors and help to explain how estrogen-responsive genes are differentially regulated by these two receptors.