Different configurations of specific thyroid hormone response elements mediate opposite effects of thyroid hormone and GC-1 on gene expression

T-3 regulates transcription of the rat sarcoendoplasmic reticulum calcium ATPase in the heart. The T-3 effect is mediated by three differently configured T-3 response elements (TREs). Here we report the mutation of each individual TRE in the promoter and the contribution of each TRE on gene expression. Mutation of TRE1, a direct repeat element, exerted the strongest T-3 response, compared with TRE2 and TRE3, which are inverted palindromes. The isolated TRE2 and TRE3, which showed no response (TRE2) or were weakly positive with T-3 ( TRE3), became strong negative regulatory elements with the T-3 analog GC-1. We found that TRE1 recruits corepressor complexes containing nuclear receptor corepressor and histone deacetylase 3 in the absence of ligand, and steroid receptor coactivator-1-containing coactivator complexes with both T-3 and GC-1. TRE3 bound the same corepressor complexes without ligand but showed only a weak association with steroid receptor coactivator-1 with T-3 and a strong association with corepressor complexes with GC-1. Thus, GC-1 appears to control cofactor association differentially on these two sarcoendoplasmic reticulum calcium ATPase TREs, which could be the mechanism of ligand-dependent transcriptional activation and repression observed with the isolated TRE1 and TRE3 elements. Because the x-ray crystal structures of GC-1 and T-3 complexed with the TR ligand binding domain are superimposable, the results imply that GC-1 and T-3 induce differential effects on the receptor that are not evident in the static structures but must occur in the dynamic setting of receptor function. These results have implications for selective modulation of receptor function by agonist ligands.