Differential Modulation of DNA Conformation by Estrogen Receptors α and β*

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 ERα and ERβ to activate transcription and induce distortion and bending in DNA. ERα induced higher levels of transcription than ERβ in the presence of 17β-estradiol. In circular permutation experiments ERα induced greater distortion in DNA fragments containing the consensus ERE sequence than ERβ. Phasing analysis indicated that ERα induced a bend directed toward the major groove of the DNA helix but that ERβ failed to induce a directed DNA bend. Likewise, the ERα DNA binding domain (DBD) and hinge region induced a bend directed toward the major groove of the DNA helix, but the ERβ DBD and hinge region failed to bend ERE-containing DNA fragments. Using receptor chimeras we demonstrated that the ERα 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 ERα and ERβ 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.

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