THYROID-HORMONE RESPONSE ELEMENT ARCHITECTURE AFFECTS COREPRESSOR RELEASE FROM THYROID-HORMONE RECEPTOR DIMERS

Thyroid hormone receptors are ligand-modulated transcription factors t hat can repress or activate transcription depending upon the absence o r presence of thyroid hormone and the nature of the hormone response e lement to which the receptors are bound. The ability of thyroid hormon e receptors to repress transcription in the absence of ligand is thoug ht to be due to associations with nuclear hormone receptor corepressor s. Ligand binding by the thyroid hormone receptor is believed to disso ciate these corepressors and recruit coactivators to promote transcrip tion from target promoters. We hypothesize that variations in response element architecture may influence both the association and dissociat ion of corepressors from DNA-bound thyroid hormone receptors. Using a chimeric corepressor, we find that ligand alone does not fully relieve corepressor-mediated repression, particularly in the presence of thyr oid hormone receptor and its heterodimerization partner, the retinoid X receptor, Interestingly, the steroid receptor coactivator 1 together with ligand is able to mediate full release of corepression, but this relief is dependent upon the architecture of the response element to which the nuclear receptor dimer-corepressor complex is bound. These s tudies suggest that other cellular factors in addition to ligand may b e required for the release of corepressors from thyroid hormone recept or dimers.